Metab Brain Dis DOI 10.1007/s11011-016-9806-1

REVIEW ARTICLE

The rise and fall of insulin signaling in Alzheimer’s disease B. Chami 1 & A. J. Steel 2 & S. M. De La Monte 3,4,5 & Greg T. Sutherland 2

Received: 4 November 2015 / Accepted: 3 February 2016 # Springer Science+Business Media New York 2016

Abstract The prevalence of both diabetes and Alzheimer’s disease (AD) are reaching epidemic proportions worldwide. Alarmingly, diabetes is also a risk factor for Alzheimer’s disease. The AD brain is characterised by the accumulation of peptides called Aβ as plaques in the neuropil and hyperphosphorylated tau protein in the form of neurofibrillary tangles within neurons. How diabetes confers risk is unknown but a simple linear relationship has been proposed whereby the hyperinsulinemia associated with type 2 diabetes leads to decreased insulin signaling in the brain, with downregulation of the PI3K/AKT signalling pathway and its inhibition of the major tau kinase, glycogen synthase kinase 3β. The earliest studies of post mortem AD brain tissue largely confirmed this cascade of events but subsequent studies have generally found either an upregulation of AKT activity, or that the relationship between insulin signaling and AD is independent of glycogen synthase kinase 3β altogether. Given the lack of success of beta-amyloid-reducing therapies in clinical trials, there is intense interest in finding alternative or adjunctive therapeutic targets for AD. Insulin signaling is a neuroprotective pathway

* Greg T. Sutherland [email protected]

1

Redox Biology, The University of Sydney, Sydney, NSW, 2006, Australia

2

Neuropathology Group, Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia

3

Department of Neurology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA

4

Department of Neurosurgery, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA

5

Department of Pathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA

and represents an attractive therapeutic option. However, this incredibly complex signaling pathway is not fully understood in the human brain and particularly in the context of AD. Here, we review the ups and downs of the research efforts aimed at understanding how diabetes modifies AD risk. Keywords Alzheimer’s disease . Type 2 diabetes . Insulin signaling pathway . Glycogen synthase kinase 3beta

Introduction Alzheimer’s disease (AD) is the most common form of dementia and is rapidly reaching epidemic proportions due to an aging population and a current lack of disease modifying therapeutics. AD clinically manifests as an early loss of short-term memory followed by the progressive loss of other cognitive domains. Pathologically AD is characterised by widespread atrophy and neuronal loss, moderate gliosis and two pathognomonic entities: extracellular neuritic plaques, composed mainly of a group of peptides called beta-amyloid (Aβ) and intraneuronal neurofibrillary tangles (NFT), chiefly made up of hyperphosphorylated species of the microtubule associated protein tau (tau). There are rare monogenic cases of AD but most cases are considered sporadic with no familial or geographic clustering. The pathogenesis of sporadic AD is unknown but like the monogenic forms, it is thought to be precipitated by the accumulation of Aβ, with the subsequent formation of NFTs and ultimately, neuronal death (Hardy and Selkoe 2002). The major current issue in AD research is that experimental treatments reducing Aβ accumulation have not been successful in slowing cognitive decline in AD patients. It has been suggested that these therapies are being instigated too late in the disease process to have a positive effect (Golde et al. 2011). Trials of earlier interventions,

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facilitated by improvements in Aβ biomarkers, are now underway but there is also considerable interest in finding alternative or adjunctive approaches to treating AD. Longitudinal cohort studies have shown that diabetes is a risk factor for both dementia and AD (Ott et al. 1999; Arvanitakis et al. 2004; Janson et al. 2004). Notwithstanding that mixed pathology is a common finding in AD brains, diabetes remains a risk factor in AD independent of its role in vascular and mixed dementia (Gudala et al. 2013) (and reviewed by(Biessels and Reagan 2015)). More recent studies in these same populations suggest that diabetes exerts its effect relatively early in the disease course as the positive associations disappear over time (Akomolafe et al. 2006; Schrijvers et al. 2010). How diabetes, and particularly type two diabetes (T2D), confers this risk is unknown but an attractive hypothesis is that it is secondary to central insulin resistance (Moreira et al. 2009). Insulin signaling occurs via the phosphatidylinositol kinase (PI3K)/protein kinase B (AKT) and Ras/mitogen activated kinase (MAPK) pathways. A major downstream target of PI3K/AKT signaling is glycogen synthase kinase 3β (GSK3β), that is also a major tau kinase. Theoretically, a decrease in insulin signaling in the brain would lead to high GSK3β activity, tau hyperphosphorylation, NFT formation and neuronal death (Correia et al. 2011). Indeed some studies have found such effects and AD has been described as type III diabetes (Steen et al. 2005). However, other work has produced conflicting data, or even challenged the direction of causation between AD and diabetes. This review explores the evidence linking diabetes, insulin signaling and AD and considers whether the PI3K/AKT pathway is a legitimate therapeutic target.

Insulin signaling The systemic regulation of glucose metabolism by insulin was discovered in 1922 (Banting et al. 1922). Insulin signaling occurs via the PI3K/AKT and Ras/MAPK pathways that facilitate the metabolic and growth promoting actions of insulin, respectively (Groop et al. 2005). Insulin activates glycogen synthase (GS) to increase glycogen production, primarily in muscles and the liver, by inactivating glycogen synthase kinase 3 (GSK3) via the PI3K/AKT pathway (Cross et al. 1995). The PI3K/AKT signaling cascade occurs when insulin binds to the insulin receptor (IR), a member of the family of tyrosine kinase receptors (Plum et al. 2005). Following ligation, a conformational change to the IR results in its autophosphorylation that attracts and phosphorylates multiple tyrosine residues on various docking proteins, including insulin receptor substrates (IRS) 1 and 2 (White 2003) (Fig. 1). IRS1/2 binds to and activates a family of signal transducing enzymes

called phosphatidylinositol −4,5-bisphosphate 3-kinases (PI3K). PI3K phosphorylates the membrane-bound lipoprotein phosphoinositide (4,5)-P2 (PIP2) to PIP3 (Vanhaesebroeck et al. 1997). PIP3 is a key molecule in this cascade because it binds and recruits both AKT and its activator phosphoinositide-dependent kinase-1 (PDPK1 aka PDK-1) to the plasma membrane (Franke et al. 1997). This binding of inactive AKT to PIP3 induces a conformational change in AKT that exposes its active loop, resulting in its phosphorylation by PDPK1 at an isoform-specific threonine (Thr-308 for AKT1) (Alessi et al. 1996). PDPK1 phosphorylation at Thr-308 stabilizes the activation loop, facilitating a second phosphorylation at the C-terminal of AKT (Ser-473 for AKT1) by the mammalian target of rapamycin (mTOR) complex-2 (mTORC2) (Sarbassov et al. 2005). This additional phosphorylation event potentiates AKT activity seven-fold, and results in its full activation (Alessi et al. 1996). Among its targets AKT phosphorylates and inactivates GSK3β, at Ser-9 (Cross et al. 1995) (Fig. 1).

Insulin signaling in the brain Although the brain represents only 2 % of the total body weight, it requires 20 % of total blood flow and consumes 25 % of the body’s glucose. 80 % of that glucose is metabolized to produce energy, in the form of adenosine triphosphate (ATP), for glutaminergic neurotransmission (Sibson et al. 1998). In insulin-sensitive tissues, insulin stimulates the uptake of glucose by accelerating the recycling of vesicles containing the glucose transporter type 4 (GLUT-4) to the cell surface (Leto and Saltiel 2012). This process involves PI3K/ AKT-dependent and independent mechanisms. Advances in neuroimaging techniques in particular have shown us that there is a fundamental problem in glucose metabolism in the AD brain (Cohen and Klunk 2014; Willette et al. 2015). However, it is important to note that unlike peripheral tissues, insulin has no effect on glucose uptake into the brain (Hasselbalch et al. 1999; Knudsen et al. 1999). Rather, glucose is continually supplied to the brain from the cerebral circulation via active transporters at the blood-brain-barrier (BBB) (Gjedde 1983). Glucose uptake into the brain relies on the facilitative and saturable carrier protein GLUT-1 in the cerebral endothelium (Pardridge et al. 1990). GLUT-1 also transports glucose from the parenchyma into glia while glucose uptake into neurons utilizes another transporter GLUT-3. Neurons can metabolize glucose directly but astrocytes are also thought to augment neuronal energy supplies by converting glucose into lactate via anaerobic metabolism and exporting it to the interstitium where neurons can then take it up (Kann and Kovacs 2007) (Fig. 1). Insulin was presumed for many years to have a limited role in the brain due to its lack of effect on glucose uptake.

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Fig. 1 Insulin signaling in the brain. A cartoon depicts some of the known and postulated roles for insulin in the human brain. The brain is classically known as an insulin insensitive organ because it does not rely on insulin for glucose uptake. Rather glucose is transported to the brain parenchyma via the glucose transporter, GLUT1 on the endothelial cells (red) of the blood-brain-barrier (BBB). GLUT1 transporters are also found on astrocytes (green) while neurons (purple) take up glucose directly from the brain parenchyma via GLUT3 or alternatively rely on lactate produced by astrocytes. Astrocytic processes are structurally and functionally involved in both synapses and the BBB and are therefore ideally, placed to coordinate cerebral blood flow with neuronal activity, a process known as neurovascular coupling. Astrocytes remove glutamate, via the glial glutamate transporter, GLAST1, from excitatory synapses and convert it to glutamine prior to its recycling back to the neurons. Insulin reaches the brain via insulin receptors/transporters at the BBB. These same receptors (IR-B) are also found on astrocytes but neurons have a slightly different isoform (IR-A). Insulin affects the brain via two

major pathways: P13K/AKT and Ras/MAPK, that are responsible for proliferative and metabolic activities respectively. A major downstream target of the P13K/AKT pathway is the enzyme, glycogen synthase kinase 3 (GSK3). This enzyme has two isoforms α and β. GSK3 is inactivated through phosphorylation by AKT that is itself upregulated by insulin signaling. In its unphosphorylated (active) form, GSK3 has multiple targets including the Alzheimer’s disease-related proteins microtubule (MT)-associated protein tau (tau) and APP. GSK3α increases the production of Aβ monomers by enhancing BACE1 (β-secretase) activity. GSK3β increases tau phosphorylation reducing its binding to microtubules. It also promotes long-term depression (LTD) or weakening of synaptic strength following its activation by protein phosphatase 1. It is not clear how GSK3β promotes LTD but it is likely to involve either the activation of NMDA receptors (NMDAR) or the endocytosis of AMPA receptors (AMPAR). Long-term potentiation inhibits GSK3β via a PI3K/ AKT-dependent mechanism

This opinion changed initially following experiments with the drug streptozotocin (STZ). STZ is a glucosamine derivative of nitrosourea that causes peripheral hyperglycemia by its toxic effects on the insulin-producing pancreatic beta cells. It was early studies with STZ-treated rats along with obese hyperinsulemic rats that showed that brain insulin and its receptors were regulated independently of those in the periphery (Havrankova et al. 1979). Havrankova and colleagues

concluded that brain insulin and insulin receptors must be synthesized by neural elements. However, as molecular and immune tools improved, further work showed that insulin, like glucose, was transported across the BBB (King and Johnson 1985; Pardridge et al. 1985) and bloodcerebrospinal fluid (CSF)-barrier (Schwartz et al. 1990) by transporters in the cerebral endothelium. In this case the transporter is the insulin receptor (IR) (Fig. 1). The contribution of

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centrally derived insulin remains controversial but most researchers consider that peripheral insulin is the major source (Freude et al. 2005). Insulin and IRs are not evenly distributed in the brain but rather concentrated in areas such as the hippocampus and hypothalamus (Havrankova et al. 1978; Steen et al. 2005). The significance of this distribution is not entirely clear although the increased density in the hippocampus is consistent with a role in learning and memory (Zhao et al. 2004b). There are two isoforms, IR-A and IR-B, which differ by the addition or exclusion of exon 11 and they display subtle differences in their signaling properties (Belfiore et al. 2009). A differentially glycosylated form of IR-A is found on neurons while glial cells and the BBB have IR-B. IRs are found in all neuronal compartments including the pre-synaptic terminals (HerasSandoval et al. 2012) and dendrites (Abbott et al. 1999; Lee et al. 2011) (Fig. 1). In the periphery, insulin and insulin-like growth factor 1 (IGF1) signal via both IRS1 and IRS2. Recent work suggests that in the brain insulin favors IRS1 while IGF1 favors IRS2 (Talbot et al. 2012) but IRS2−/− mice have the neurological phenotype displaying a normal body size but unexpectedly small brains (Schubert et al. 2003). The male IRS2−/− mice also die at 10–15 weeks from severe hyperglycemia while females survive to six months of age. In contrast, IRS1−/− mice are born at 50 % of normal size but only develop mild T2D (Araki et al. 1994). On histopathological examination, IRS2−/ − mice have a third fewer neurons than their wild-type littermates while residual neurons in older animals display tau hyperphosphorylation and NFTs. Schubert et al. noted that tau was particularly phosphorylated at Ser-202, a known site for GSK3β, and this was consistent with decreased insulin signaling. However, GSK3β was also phosphorylated at its inhibitory Ser-9 site suggesting that it could not be directly responsible for tau hyperphosphorylation. The latter finding was also reported in some AD brains suggesting that alternative kinases or upregulation of tau phosphatases such as protein phosphatase (PP) 2A are involved. An important role of insulin in the brain is the regulation of feeding. Mice with neuron-specific disruption of the IR display increased feed intake (females only), obesity, hyperleptinemia, insulin resistance, and hypertriglyceridemia (Bruning et al. 2000). Bruning et al. suggested that insulin in the brain facilitates the post-prandial inhibition of food intake by increasing resistance to the anorexic hormone, leptin. Both leptin and insulin act as peripheral indicators of energy balance and both regulate PI3K signaling in hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AGRP) neurons. They have the same effect on POMC but opposing effects on AGRP neurons (Xu et al. 2005). Leptin can also rescue insulin-deficient mice (Yu et al. 2008), via a leptin receptor-dependent mechanism involving POMC and hypothalamic GABA neurons (Fujikawa et al. 2013).

Hypothalamic neurons monitor blood nutrient concentrations and communicate with insulin-sensitive organs such as the liver and pancreas via both neural and humoral routes to play a role in peripheral glucose metabolism (Buijs et al. 2001; Obici et al. 2002; Lam et al. 2005a; Lam et al. 2005b). Whether they are involved in the relationship between diabetes and AD is discussed further below. In terms of cognition, insulin acts as a neurotrophic and neuroplastic factor, akin to the IGF1 and 2. Yet, like its role in the periphery, it still utilizes the PI3K/AKT and Ras/MAPK pathways to achieve these functions (Banks et al. 2012). Long-term potentiation (LTP) and long-term depression (LTD) are models of hippocampal memory formation (Bliss and Collingridge 1993; Collingridge et al. 2010). Impaired insulin receptor signaling decreases experience-dependent plasticity (Chiu et al. 2008) with IRS2−/− mice demonstrating impaired LTP (Martin et al. 2012) (Fig. 1). The facilitation of LTP by neurotrophic factors is not peculiar to insulin or IGF1. Leptin also appears to upregulate LTP via activation of the PI3K/AKT and MAPK (Shanley et al. 2001). In contrast, nerve growth factor (Conner et al. 2009) and brain-derived neurotrophic factor (BDNF) (Ying et al. 2002) facilitates hippocampal plasticity via another family of receptor tyrosine kinases, the tropomyosin sensitive receptor kinases (Trk) receptors. The Trk receptors work in conjunction with the neurotrophin receptor, p75NTR, to stimulate signaling cascades including the PI3K/AKT pathway (Mai et al. 2002). Levels of BDNF, in particular, are reduced in the AD brain (Phillips et al. 1991; Connor et al. 1997) but it was the functionally-related nerve growth factor (NGF), with its potential sparing of cholinergic neurons in the basal forebrain, that was the first growth factor tested in clinical trials; these remain ongoing (Allen et al. 2013). The relative importance of insulin in modulating synaptic plasticity in the adult brain remains unknown but it is interesting to note that AD is characterized by the early loss of short-term memory and Aβ appears to have the opposite effects on LTP and LTD, a phenomenon that will be revisited later.

AKT Since its discovery in 1987 as the human homologue of the viral oncogene v-AKT, many physiological roles have been attributed to AKT (Bellacosa et al. 1991; Vanhaesebroeck et al. 1997). The serine/threonine kinase (also referred to as Protein Kinase B) belongs to a family of kinases approximately 57 kDa in size. To date, three human isoforms have been described: AKT1 (PKBμ), AKT2 (PKBβ) and AKT3 (PKBγ) (Dummler and Hemmings 2007). All AKT isoforms contain three important domains crucial for their kinase activity: the N-terminal pleckstrin homology (PH) domain that interacts with PIP3, a central kinase domain

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and a carboxyl-terminal regulatory domain that contains a hydrophobic motif (HM) (Barnett et al. 2005; Zhou et al. 2006). A threonine (Thr-308 in AKT1, Thr-309 in AKT2 and Thr-305 in AKT3) and a serine (Ser-473 in AKT1, Ser474 in AKT2 and Ser-472 in AKT3) residue located within the latter two domains undergo reversible phosphorylation that, in part, regulates AKT kinase activity (Fayard et al. 2005) (Fig. 2). The expression of the three AKT isoforms varies widely between different tissues, cell types and subcellular localization (Dummler and Hemmings 2007). AKT1 is ubiquitously expressed, AKT2 is preferentially expressed in insulinsensitive tissues such as skeletal muscle, adipose tissue and

liver while AKT3 is largely restricted to the adult brain, kidney and lung (Brodbeck et al. 1999). AKT3 null mice have a selective reduction of brain volume along with brain cell size and density (Easton et al. 2005). The Allen Human Brain Atlas suggests that AKT3 is the predominant isoform in the human brain with AKT1 mRNA levels being relatively low (Hawrylycz et al. 2012). AKT is multifunctional. Its proapoptotic substrates include BAD (Blume-Jensen et al. 1998; Gardai et al. 2004) caspase-9 (Cardone et al. 1998) and apoptosis signal-regulating kinase 1 (Kim et al. 2001). Metabolism-related AKT substrates include the gluconeogenic transcription factors, forkhead box O-3α (FOXO3α) (Brunet et al. 1999) and FOXO1 (Rena et al.

Fig. 2 Insulin signaling, the PI3K/AKT pathway and Alzheimer’s disease. In neurons of a normal brain, insulin binds to and induces autophosphorylation of the insulin receptor (IR). This sets in motion a signaling cascade that phosphorylates and activates the kinase AKT. A major downstream target of AKT is GSK3 with its two isoforms, α and β. GSK3 has multiple substrates including glycogen synthase (in astrocytes) and the Alzheimer’s disease-related proteins, APP and tau. In Alzheimer’s disease (indicated by red crosses and arrows) excess Aβ production and/or its insufficient clearance from the neuropil results in the formation of soluble Aβ oligomers (AβO). These extracellular AβO eventually form plaques but also interact with the neurons to

downregulate their insulin signaling. Extracellular AβO may perturb insulin signaling via competing for binding with the insulin degrading enzyme (IDE), blocking the IR directly or increasing its endocytosis. The intracellular accumulation of AβO in organelles such as multivesicular bodies may also play a role in neuronal dysfunction. Similarly peripheral insulinemia in type 2 diabetes results in the downregulation of IRs and insulin activity in the brain. Diabetes and AβO may therefore act synergistically to decrease AKT activity and increase unphosphorylated GSK3β (active form). Subsequently overactive GSK3β is postulated to hyperphosphorylate tau and lead to its tau selfaggregation, NFT formation and neuronal death

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1999). AKT also inhibits tuberous sclerosis 2 (TSC2) (Inoki et al. 2002), part of the TSC complex that is a major inhibitor of mTOR complex 1 (mTORC1) (Fig. 2). AKT therefore activates mTORC1, a positive regulator of anabolism (Howell et al. 2013). In a negative feedback loop, mTORC1 also inhibits PI3K/AKT activity via phosphorylation of the IRS proteins (Huang and Manning 2009). The phosphorylation of IRS1 by mTORC1 and other serine kinases is discussed further below. In contrast, the rapamycin-insensitive mTORC2 activates AKT by phosphorylation at Ser-473 (Sarbassov et al. 2005). Paradoxically, the TSC complex also activates mTORC2 providing a further negative feedback on insulin signaling (Huang and Manning 2009). In insulin sensitive tissues, AKT phosphorylates and inactivates GSK3β (Ser-9) upregulating glycogen synthesis. mTORC1 inhibits protein phosphatase 2 A (PP2A), an enzyme that operates reciprocally with AKT to regulate GSK3β phosphorylation at Ser-9 (Fig. 1). By inhibiting TSC2 and PP2A activity AKT also has an indirect means to decrease GSK3β activation (Meske et al. 2008).

GSK GSK3 has two isoforms, α and β. There is likely to be some level of, or even complete, redundancy between these two isoforms but the field has lacked isoform-specific inhibitors to confirm or refute this assumption (Doble et al. 2007). Nevertheless most research into both the physiological role of GSK3 in the brain and in AD has concentrated on GSK3β (Ma 2014). GSK3 was first recognized as the enzyme responsible for the rate-limiting step in glycogen synthesis (Embi et al. 1980; Rylatt et al. 1980). Multiple substrates have now been identified, including amyloid precursor protein (APP) (Aplin et al. 1996), collapsin response mediator protein 2 (CRMP2), c-myc, β-catenin, (Soutar et al. 2010), Bax (Linseman et al. 2004), presenilin 1 (Twomey and McCarthy 2006), IRS1 (Eldar-Finkelman and Krebs 1997) and tau (Hanger et al. 1992). GSK3β phosphorylates and inactivates its targets or primes them for degradation (e.g. β-catenin, cyclin D1 and the oncogene c-myc) resulting in the inhibition of glycogen synthesis, transcription and proliferation. A distinctive feature of GSK3 is that it often requires its substrates to be primed by other kinases such as CDK5 (Cole et al. 2006). GSK3β promotes apoptosis by destabilizing MCL1 (Maurer et al. 2006), a member of the Bcl-2 family, and transcription factors such as microphthalmia-associated transcription factor and upstream stimulating factor 1 that coordinate activities with the AKT-inactivated FOXO (Terragni et al. 2011). GSK3β also activates p53 via phosphorylation of the histone acetyltransferase, Tip60 that then acetylates and activates p53 (Nayak and Cooper 2012) (Fig. 2).

GSK3β is also a major regulator of LTP and the key molecule in LTD (Peineau et al. 2007). LTP in the hippocampus is the result of N-methyl-D-aspartate (NMDA) receptordependent insertion of new α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors into the dendritic membrane (Lu et al. 2001; Ahmad et al. 2012) (Fig. 1). During LTD, GSK3β activity is increased due to dephosphorylation of Ser-9 by protein phosphatase 1 (Peineau et al. 2007). How GSK3β promotes LTD is unknown but it appears to phosphorylate and activate proteins involved in the endocytosis of AMPA receptors such as kinesin light chain 2 (Du et al. 2010; Bradley et al. 2012) (Fig. 2). In contrast, the downregulation of GSK3β by AKT during LTP is predicted to preserve the information encoded from erasure by subsequent LTD (Peineau et al. 2007). Like AKT, the activity of GSKβ is regulated by phosphorylation (Hughes et al. 1993), although phosphorylation at Ser9 inhibits rather than activates its activity (Sutherland et al. 1993). Furthermore, the majority of Ser-9 GSKβ inhibition occurs via the PI3K/AKT pathway (Cross et al. 1995). In contrast, tyrosine phosphorylation of GSK3β at position 216 increases kinase activity (Hughes et al. 1993). The kinase(s) involved with the latter have not been fully elucidated but FYN is thought to be involved (Lesort et al. 1999) (Fig. 2). FYN also phosphorylates (Tezuka et al. 1999) and stabilizes NMDA receptors at the post-synapse (Trepanier et al. 2012). FYN is required for Aβ neurotoxicity and relies on tau for its transport to the post-synapse (Ittner et al. 2010). Given that Aβ neurotoxicity is a tau-dependent process (Roberson et al. 2007; Roberson et al. 2011) Ittner et al. suggested that FYN is the link between tau and Aβ in AD. Tau is also known to interact with PIN1 at the post-synapse (Souter and Lee 2010). It may be purely coincidental but PIN1 stimulates dephosphorylation of tau at CDK5 resistant sites (Kimura et al. 2013). CDK5 sites are known to be more resistant to dephosphorylation than GSK3 sites on CRMP2 (Cole et al. 2008). The regulation of insulin signaling relies on two key molecules, IRS1 and PTEN (Fig. 2). Perhaps most important is the balance between tyrosine and serine phosphorylation of IRS. IR phosphorylation of IRS1 at twin tyrosines generates the docking sites for PI3K (Esposito et al. 2001). However, IRS serine/threonine residue (S/T) phosphorylation is also complex with more than 50 S/T sites and the phosphorylation of some sites appearing to both enhance and attenuate insulin signaling (Copps and White 2012). Auto-regulation of insulin signaling occurs when insulin activates serine kinases such as c-Jun N-terminal kinase (JNK), ERK, protein kinase C and, as discussed above, mTORC1, via S6 kinase 1 phosphorylate specific serine sites on IRS1 to inhibit its own function (Copps and White 2012). Unlike mTORC1, mTORC2 responds to insulin signaling by phosphorylating and activating AKT at Ser-473 (Oh and Jacinto 2011). mTORC2 may also be directly activated by PIP3 (Gan et al. 2011). However, like

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mTORC1, mTORC2 also provides negative feedback to the insulin signaling pathway by assisting in the proteasomal degradation of IRS1 (Kim et al. 2012). Phosphatase and tensin homolog (PTEN), a PIP3 phosphatase and tumor suppressor gene, inhibits AKT activation by dephosphorylating PIP3 to PIP2, reducing the total pool of PIP3 available for AKT activation (Simpson and Parsons 2001). PTEN is activated by GSK3β via phosphorylation at Ser-362 and Thr-366 after priming by casein kinase 2 (AlKhouri et al. 2005). Insulin and IGF1 signaling inactivates GSK3β, decreasing PTEN Thr-366 phosphorylation and activity. PTEN has an inhibitory effect on LTP, possibly via interaction with postsynaptic density-95 (PSD-95) (Jurado et al. 2010), the postsynaptic protein that also facilitates NMDA receptor phosphorylation by FYN (Tezuka et al. 1999) (Fig. 2). Overall, insulin signaling via the PI3K/AKT pathway is the subject of a multi-layered and exquisite regulatory apparatus.

The AD brain The AD brain is characterized by the progressive deposition of fibrillar Aβ in the form of extracellular plaques and hyperphosphorylated tau as intraneuronal NFTs, along with gliosis and neuronal loss. Insoluble Aβ also accumulates in the cerebral vasculature in 80 % of AD cases (cerebral amyloid angiopathy (CAA)) (Ellis et al. 1996). Plaques, NFTs and CAA are also seen in aged non-demented controls, and although this is usually at a much lower extent, it does mean that the neuropathological diagnosis of AD remains one of probability rather than being definitive (Montine et al. 2012). The progression of AD pathology, particularly tau pathology occurs in a predictable pattern with NFTs forming first in the allocortex (transentorhinal and entorhinal cortex), then spreading to temporal and frontal neocortices and lastly involves the primary cortices (Braak and Braak 1991; Arriagada et al. 1992). At post mortem, ‘probable’ AD cases display up to 90 % neuronal loss in parts of their entorhinal cortex (Gomez-Isla et al. 1996) whereas the complement of neurons in primary cortices such as the primary visual cortex (PVC) remain largely intact (Iacono et al. 2008). In contrast, Aβ pathology is initially seen throughout the ventral neocortex including the occipital lobe and PVC before spreading into the parahippocampal formation (Braak and Braak 1991; Thal et al. 2002). As a consequence many regions of the AD brain do not follow an BAβ pathology first, tau pathology second^ relationship as might be expected from the popular amyloid cascade hypothesis (discussed below). The molecular age of AD research began when Aβ was purified from AD brains (Glenner and Wong 1984; Masters et al. 1985) and from individuals with trisomy 21 (Down syndrome) (Masters et al. 1985). Shortly afterwards, the APP

gene was cloned (Kang et al. 1987). The APP gene is found on chromosome 21 and all Down syndrome patients develop AD pathology with Aβ deposition from as early as eight years of age (Lott 2012). This suggested to researchers that gene multiplications of APP might be also responsible for familial forms of AD. As it turned out, APP missense mutations were discovered first (Goate et al. 1991), but rare gene duplications were subsequently found (Rovelet-Lecrux et al. 2006). Aβ emanates from the sequential β- and γ-secretase proteolytic cleavages of APP (Zhang and Song 2013). Mutations in individuals with autosomal dominant inherited forms of AD were also found in two additional genes, PSEN1 and PSEN2 encoding presenilin 1 and 2 respectively. Either one of the two presenilins are one of four proteins that make up the intramembrane protease complex, γ-secretase. All these mutations promote the so-called amyloidogenic pathway and the production of the longest and most aggregative Aβ peptide, Aβ1–42 over the normally more common Aβ1–40 (St GeorgeHyslop 2000). The physiological role of APP is unknown but is thought to be a neurotrophic factor (Dawkins and Small 2014). Aβ is largely regarded as a degradation product, with no physiological role, although its production is highly correlated with neuronal activity (Kamenetz et al. 2003; Bero et al. 2011). However, in vitro models hint that soluble Aβ oligomers (AβO) may have a physiological role in modulating synaptic plasticity by promoting LTD over LTP (Taylor et al. 2008; Parihar and Brewer 2010). Although speculative, it is possible that the various degradative products of APP, rather than the protein itself, mediate its neurotrophic effects. Furthermore these reciprocal effects could be mediated, in part, via the PI3K/AKT pathway (Jimenez et al. 2011). Unlike APP, tau’s physiological role is well known. Along with other microtubule-associated proteins, such as MAP1B and MAP2, tau binds to and stabilizes microtubules (de Forges et al. 2012), analogous to railroad ties (sleepers) on a railroad track. Microtubules are dynamic structures constantly growing and shrinking with the polymerization and then depolymerization of their tubulin Monomers. tau binding is therefore also required to be dynamic and this is regulated by its phosphorylation status. Pathological conditions favoring hyperphosphorylation of tau, particularly in its microtubule binding domains, result in tau’s detachment from microtubules and self-aggregation (Kosik et al. 1986) (Fig. 2). Despite research progress, the etiopathogenesis of sporadic AD remains poorly understood. The robust amyloid cascade hypothesis, based on the monogenic cases of AD, suggests that AβO initiates the disruption of neuronal signaling pathways and the kinase/phosphatase balance leading to abnormal tau hyperphosphorylation and NFT formation (Hardy and Higgins 1992; Hardy and Selkoe 2002). The corralling of tau into granules and then NFTs within the neuronal soma along with other accidental proteins initially compromises

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neuronal function. However, as they build up the NFT and dystrophic neurites in the axons eventually prohibit all cellular activity, resulting in neuronal death and insoluble tau remnants (‘ghost’ tangles) left in the parenchyma (Uchihara et al. 2001). The major tau kinases include GSK3β (Sperber et al. 1995), cyclin-dependent kinase (CDK5) (Baumann et al. 1993), MAPK (Greenberg et al. 1994) and FYN (Lee et al. 2004), while tau phosphatases include PP1 (Gong et al. 1994), PP2A and calcineurin (PP2B) (Drewes et al. 1993).

Diabetes and AD Diabetes, along with aging and the APOE ε4 allele, is one of the few replicable risk factors known for sporadic AD (Sutherland et al. 2011b). Paradoxically, the chronic peripheral hyperinsulinemia associated with type 2 diabetes (T2D) results in a compensatory decrease in brain insulin. This is due to the downregulation of insulin receptors (transporters) at the BBB (Moreira 2012). Pathological studies in the postmortem AD brain have shown decreases in the insulin signaling apparatus (Steen et al. 2005; Freude et al. 2009; Moloney et al. 2010; Bomfim et al. 2012; Talbot et al. 2012) and the term BType 3 diabetes^ was coined to describe AD (Steen et al. 2005) (Fig. 2). Certainly Type 1 diabetes and T2D are associated with cognitive impairment and although the temporal context and relationship with co-morbidities such as obesity differ between the two forms the effect on cognition is largely thought to relate to glycemic control (Moheet et al. 2015). Nevertheless, the most popular hypothesis for how diabetes modifies AD risk remains that the downregulation of insulin signaling in the AD brain enhances GSK3 activity and tau phosphorylation. The major ‘Achilles heel’ of this hypothesis is that diabetics generally do not develop AD pathology (Heitner and Dickson 1997; Alafuzoff et al. 2009). Consistent with the amyloid cascade hypothesis, a number of potential interactions between Aβ and insulin have been proposed that mechanistically link insulin resistance to AD. Firstly, Aβ and insulin are both substrates for the insulin degrading enzyme (IDE) (Gasparini et al. 2001). IDE is upregulated by insulin and this may explain the seemingly paradoxical relationship between decreased brain insulin and increased Aβ (Zhao et al. 2004a). Second, insulin can prevent the oligomerization of Aβ (Lee et al. 2009a). Third, AβO can competitively bind to the IR and block the insulin signaling pathway (Xie et al. 2002; Townsend et al. 2007). There is also reasonable evidence that AβO indirectly downregulates IRs at the plasma membrane via binding to other, as yet defined, receptors (Zhao et al. 2008; De Felice et al. 2009). Others have suggested that competition between insulin and Aβ occurs further downstream with Aβ blocking the interaction between PDPK1 and AKT (Lee et al. 2009b) or Aβ and insulin having reciprocal effects on mitochondrial function by the promotion

or attenuation of oxidative stress and apoptosis respectively (Moreira 2012) (Fig. 2). Experiments involving STZ were fundamental in defining the unique nature of insulin’s role in the brain. STZ has also been used to try and understand the relationship between diabetes and AD (de la Monte et al. 2006). Peripheral STZ administration exacerbates tau pathology in transgenic mutant tau mice (Ke et al. 2009). Ke et al. suggested tau hyperphosphorylation could have resulted from decreased phosphatase activity, hypothermia, or other metabolic abnormalities as a result of either insulin deficiency or high brain glucose levels or both. More recently it was shown that the synaptic anomalies and cognitive impairments in mice treated with peripheral STZ were not seen in mice without endogenous tau (Abbondante et al. 2014). Addondante and colleagues demonstrated that both wild-type and tau knock-out mice had decreased p-PI3K and p-AKT, and increased pGSK3β (Ser-9) in their brains confirming that tau was the crucial target of insulin deficiency. Unlike the type 1 diabetes model above, the intracerebroventricular injection of STZ and other diabetogenic compounds mimics the proposed relationship between T2D and AD (Lester-Coll et al. 2006) with increased GSK3β activity and tau phosphorylation (Deng et al. 2009). It also results in metabolic deficits and impairments to learning and memory in rodents (Hoyer and Lannert 1999), similar to those seen in AD (Salkovic-Petrisic et al. 2013). STZ’s mechanism of action in the brain is unknown but it is thought to decrease autophosphorylation of the IR (Kadowaki et al. 1984; Hoyer et al. 1994). However, STZ also downregulates glycolytic enzyme activity (Plaschke and Hoyer 1993), increases oxidative phospholipid breakdown (Nitsch et al. 1998) and reduces antioxidant capacity (Sapcanin et al. 2008).

Insulin signaling and AD Lower levels of both the IR (Steen et al. 2005) and IRS1/2 (Steen et al. 2005; Moloney et al. 2010; Bomfim et al. 2012) have been demonstrated in the AD brain. Given the proposed linear relationship between insulin resistance, tau hyperphosphorylation and NFT formation in sporadic AD, one would expect a downregulation of p-AKT (Ser-473) in the AD brain and animal models (Fig. 2). Indeed, an initial study by Steen et al. did show that insulin signaling and pAKT were downregulated in the AD brain (Steen et al. 2005), a finding that has since been replicated (Liu et al. 2011). Furthermore, p-AKT (Ser-473) was further downregulated in the brains of AD patients with co-morbid diabetes (Liu et al. 2011). However, other studies utilizing post mortem tissue have found the opposite, where the insulin signaling pathway, and particularly AKT activity was upregulated in AD (Pei et al. 2003; Rickle et al. 2004; Griffin et al. 2005). Increased

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AKT activity has also been reported in temporal cortex neurons in the AD brain, and this correlated positively with Braak staging, a measure of the extent and distribution of NFTs (Rickle et al. 2004). Griffin et al. showed increased p-AKT (Ser-473) in the particulate fraction (membrane bound proteins) of AD homogenates (Griffin et al. 2005). Their subcellular fractionation approach also showed that (residual) cytosolic AKT was decreased in AD. They concluded that the relocation of p-AKT (Ser-473) to the plasma membrane was consistent with an overall increase in AKT activity in the AD brain. The other studies did not fractionate their homogenates and this, to some extent, might explain the discrepancies in results. In vitro studies established GSK3β, as a major tau kinase (Hanger et al. 1992; Mandelkow et al. 1992; Ishiguro et al. 1993). Phosphorylation of tau by GSK3β reduced tau’s physiological role in promoting microtubule assembly (Utton et al. 1997) whereas insulin and insulin-like growth factor-1 stimulation has the opposite effect (Hong and Lee 1997). Active forms of GSK3α/β were associated with granulovacuolar degeneration in the hippocampus and coincided with tau phosphorylated at Ser-262 and Thr-212/Ser-214, proposed sites for GSK3 (Leroy et al. 2002). Pei and colleagues demonstrated that GSK3 protein levels, although not its activity, were increased in AD brains compared to controls (Pei et al. 1997). They went on to show that active p-GSK3β (Tyr-216) accumulated in the cytoplasm of pre-tangle neurons and correlated with the progression of NFTs across the brain (Pei et al. 1999). Steen and colleagues also found increased p-GSK3β (Tyr216) levels in the AD brain that coincided with decreased IRS, PI3K and (active) p-AKT (Ser-473) levels (Steen et al. 2005). In contrast, Pei and colleagues found that increased GSK3β (Tyr-216) levels coincided with increased p-AKT (Ser-473) (Pei et al. 2003). Similarly, Griffin et al. reported increased (inactive) p-GSK3β (Ser-9) in the AD brain (Griffin et al. 2005). Ferrer et al. demonstrated that p-GSK3β (Ser-9) was highly expressed in neurons with NFTs and dystrophic neurites (Ferrer et al. 2002). Leroy and colleagues reinforced their in vitro findings above, by showing that the majority of neurons with pre-tangles were p-GSK3β (Tyr216)-positive in the frontal cortex (Leroy et al. 2007). A simple interpretation of these studies is that GSK3β is active in the early development of tau pathology but downregulated later in the disease course. Indeed Talbot and colleagues found that the levels of inactive p-GSK3β (Ser-9) in CA1 region of the hippocampus correlated with the density of NFTs (Talbot et al. 2012). However, they would develop a very different hypothesis about how perturbations in insulin signaling originate in AD as will be discussed below. Studies involving human post mortem brain tissue are inherently retrospective and it is difficult to determine disease Bcause^ from Beffect^. In contrast, animal models allow the ‘pathogenesis’ of the disease to be followed prospectively but

studies in AD models have also shown both the expected decreases in AKT activity (Hong and Lee 1997; Ho et al. 2004; Schubert et al. 2004; Lee et al. 2009b; Jo et al. 2011; Heras-Sandoval et al. 2012; Yang et al. 2013) and increases in p-AKT (Ser 473) (Pei et al. 2003; Grunblatt et al. 2007; Zhao et al. 2008; Chiang et al. 2010). Jimenez et al. showed that levels of inactive p-GSK3β (Ser-9) were increased in the 6month PS1 × APP hippocampus but then decreased in aged (18 months) mice (Jimenez et al. 2011). They proposed that earlier in the disease, the soluble amyloid precursor protein-α (sAPPα) acted via the PI3K/AKT pathway to upregulate p-AKT (Ser-473) inhibiting GSK3β whereas in the aged mice insulin signaling was blocked by AβO. A scenario that appears opposite to the consensus reached from human tissue studies where inactive p- GSK3β coincided with NFTs and dystrophic neurites. These discordant results could reflect the complexity of this signaling pathway with its multiple checks and balances. In particular IRS1 and PTEN play a key role in the regulation of insulin signaling. In the proposed setting of insulin resistance and decreased AKT activity in the AD brain, one might expect an increase in PTEN activity. Indeed, studies utilizing AD brain tissue have shown increased PTEN expression (Rickle et al. 2006; Gupta and Dey 2012) (Fig. 2). Rickle and colleagues showed a significant decrease in the levels of inactive p-PTEN (Ser-380) in the temporal cortex of AD brains, although there were no changes in total PTEN levels. However, in contrast, Griffin et al. found a decrease in PTEN levels in the AD brain. Similarly, overexpressing of PTEN in vitro studies resulted in decreased tau phosphorylation and aggregate formation (Kerr et al. 2006; Zhang et al. 2006). Kerr and colleagues further demonstrated that PTEN’s effect on tau was via reduced ERK1/2 activity and not via PI3K/AKT signaling (Kerr et al. 2006). Although PTEN is generally regarded as a potent inhibitor of AKT, Gupta et al. suggested that PTEN could positively regulate neuronal insulin signaling and glucose uptake (Gupta and Dey 2012). They postulated that this effect was via its phosphatase actions on focal adhesion kinase (FAK) and extracellular signalregulated kinase (ERK), both negative regulators of insulin/ PI3K/AKT signaling. Talbot et al. showed in the AD hippocampus that multiple serine residues on IRS1 were phosphorylated, resulting in its inactivation (Talbot et al. 2012). They suggested that central insulin resistance has a Bbottom-up^ rather than Btop-down^, contribution to AD pathogenesis. That is AD pathology causes central insulin resistance rather than vice versa. Specifically, IRS1 inactivation was Aβ-dependent where excess AβO resulted in upregulation of serine kinases such as S6K1 and GSK3β. AβO promotion of insulin resistance, as suggested by Talbot and colleagues, may even extend to AD pathology driving type 2 diabetes (T2D) rather than vice versa (Janson et al. 2004). A further study found that transgenic

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APP/PS1 mutant mice on leptin-deficient background have a predisposition to T2D without the associated metabolic traits (Jimenez-Palomares et al. 2012). Jimenez-Palomares and colleagues suggested that Aβ overproduction, results in either hypothalamic insulin resistance or excess plasma Aβ that impairs pancreatic β cell function, a conclusion supported by some clinical studies (Zhang et al. 2012). However, the fact that the hypothalamus is damaged relatively late in the disease process (Steen et al. 2005) combined with the epidemiological studies, suggesting that diabetes increases AD risk early in the disease course (Akomolafe et al. 2006; Schrijvers et al. 2010) seem to make a reverse causation between AD and diabetes less likely.

AD pathogenesis may be independent of the PI3K/AKT pathway Up to this point, the review has assumed that the relationship between diabetes and Aβ involves perturbation of the neuronal PI3K/AKT. One alternative hypothesis is that perturbations in components of the PI3K/AKT pathway may come about via mechanisms not directly related to insulin signaling. For example, GSK3β is also a critical component of Wnt/βcatenin pathway where it phosphorylates and targets βcatenin for degradation by the ubiquitin proteasome system (Aberle et al. 1997). Wnt signaling favors cytoplasmic accumulation of β-catenin and transcription, particularly important in promoting progenitor cell division and axis formation during the embryological period. In contrast, activation of the pro-apoptotic GSK3β, promotes β-catenin degradation (Aberle et al. 1997). As might be expected AKT/GSK3β signaling regulates Wnt/β-catenin signaling (Verheyen and Gottardi 2010) while activation of Wnt/β-catenin signaling increases insulin sensitivity (Abiola et al. 2009). The role of Wnt/β-catenin pathway in AD and crosstalk with insulin/IGF pathways is unknown however another potential link is that presenilins are involved in Wnt signaling and PS1 mutations perturb the trafficking of β-catenin (Nishimura et al. 1999). However the nature of their potential relationship with sporadic AD remains unknown as Maesako et al. demonstrated that presenilins decrease insulin signaling by inhibiting IR expression but that this effect was independent of both γsecretase and Wnt/β-catenin signaling (Maesako et al. 2011). Their follow-up study revealed that phosphorylated and active PS1 was negatively correlated with IR levels in human brain samples (Maesako et al. 2012). A second alternative or perhaps adjunctive hypothesis is that GSK3β phosphorylates APP directly, increasing Aβ production (Pierrot et al. 2006; Rockenstein et al. 2007). Alternatively GSK3α was shown to increase Aβ production by upregulating γ-secretase activity (Phiel et al. 2003) although more recently these associations with either isoform

and APP proteolysis have been challenged (Jaworski et al. 2011). Work in a transgenic AD mice model suggested that GSK3β upregulates BACE1 (β-secretase) expression with inhibition of GSK3β reducing Aβ pathology (Ly et al. 2013). Recently, the introduction of stem cell technologies to medical research has allowed the development of patientderived neurons via induced pluripotent stem cells (Ooi et al. 2013). Work in neurons from patients with PS-1 mutations and sporadic AD has shown strong correlations between Aβ1– 40, GSKβ and p-tau/total tau levels (Israel et al. 2012). βsecretase but not γ-secretase inhibitors significantly reduced GSKβ and p-tau/total tau levels in these cells suggesting that APP degradation products other than Aβ may induce GSKβ activity and tau phosphorylation. A third alternative hypothesis is that diabetes impacts on AD via exacerbation of cerebrovascular pathology. Hyperglycaemia and insulin resistance act on the endothelium and vascular wall similarly to high cholesterol and smoking to promote atherosclerosis (Rask-Madsen and King 2013). The role of vascular pathology in AD is controversial but many AD cases (where current neuropathological criteria are satisfied (Montine et al. 2012)) present at post mortem with vascular pathology and particularly microvascular damage (Gorelick et al. 2011; Kovacs et al. 2013; Toledo et al. 2013). In one review of 4629 AD cases, approximately 30 % had cerebrovascular disease damage at a level deemed sufficient to affect cognition (Toledo et al. 2013). The degree of vascular pathology increases with age but is also inversely correlated to Braak staging in AD cases suggesting an additive effect on dementia (Jellinger 2013; Toledo et al. 2013). It is possible that previous epidemiological studies linking diabetes and AD were confounded by cases with mixed pathology although a recent review (Ninomiya 2014) and meta-analysis (Gudala et al. 2013) of this area does suggest that diabetes is a risk factor for AD, independent of its role in vascular dementia.

Are Aβ and insulin physiological antagonists? AD is many years in the making, meaning that the etiological agent may be extremely subtle or a physiological process that slowly goes awry as its checks and balances gradually fall away with aging. In the latter respect the potential relationships between insulin Aβ and tau are intriguing. AD is primarily a synaptic disease (Selkoe 2002) and it manifests initially as short-term memory loss. NMDA receptor-dependent LTP is the working hypothesis for short-term memory formation in the hippocampus (Bliss and Collingridge 1993). GSK3β appears to act as a molecular switch between LTP and LTD, with the former inhibiting the latter via upregulation of GSK3β activity (Peineau et al. 2007; Bradley et al. 2012) (Fig. 3). LTD also requires the phosphorylation of proteins such as tau (Kimura et al. 2014), although

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Fig. 3 Synaptic plasticity, insulin signaling and Alzheimer’s disease. This cartoon explores a potential role for insulin signaling in synaptic plasticity and how such processes might be perturbed in AD. Synaptic plasticity results from two competing processes, long-term potentiation (LTP) and long-term depression (LTD). Insulin signaling augments LTP by downregulating GSK3β activity in a PI3K/AKT-dependent manner. GSK3β activity is thought to promote LTD in a number of ways including a) phosphorylating tau and b) phosphorylating kinesin light chain 2, a subunit of the transport protein, kinesin-1, activating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis. Aβ oligomers (AβO) are known to promote LTD by disrupting

neuronal glutamate uptake, and upregulating caspase-3 activity, which degrades AKT, and directly downregulating insulin signaling at the insulin receptor level. Similarly, phosphatase and tensin homolog (PTEN), promotes LTD by inhibiting AKT. The post-synaptic kinase, FYN, promotes LTP by phosphorylating post-synaptic density protein 95 (PSD-95) and stabilising N-methyl-D-aspartate receptor (NMDAR). Tau is necessary to deliver FYN to the post-synapse. In AD there is a decrease in insulin signaling and increase in AβO, hyper-phosphorylated tau and synaptic depression. This may result from the chronic promotion of LTD over LTP, a physiological process gone awry

it is unclear what role tau plays. A potential physiological role for AβO in promoting LTD over LTP was discussed above and this process involves increased GSK3β signaling (Li et al. 2009). Aβ inhibition of LTP also involves caspase-3, which cleaves AKT thereby removing its inhibition of GSK3β (Jo et al. 2011). NMDA receptor-dependent LTD also results in the activation of caspase-3 and this can be prevented by the overexpression of anti-apoptotic proteins (Li et al. 2010). As discussed above Aβ toxicity requires tau (Roberson et al. 2007), GSK3β and NMDA receptors (Decker et al. 2010; Wang et al. 2013). Furthermore FYN, a possible link between Aβ and tau in AD pathogenesis (Ittner et al. 2010), is also necessary for LTP (Grant et al. 1992) where it stabilizes NMDA receptors in the postsynaptic density by phosphorylating PSD-95 (Tezuka et al. 1999) (Fig. 3). In contrast, insulin promotes LTP (Izumi et al. 2003), at least in the immature brain (Zhao et al. 2010), as

hippocampal LTP is impaired in IRS2−/− mice (Martin et al. 2012). Insulin is able to rescue hippocampal LTP impairment induced by Aβ (Lee et al. 2009a), although the mechanism appears to be via the prevention of Aβ oligomerization. It is therefore somewhat surprising that insulin has also been shown to induce LTD by facilitating the internalization of AMPARs (Man et al. 2000). This apparent contradiction may be explained by the preceding stimulation frequency (van der Heide et al. 2005) or it may reflect our incomplete knowledge of the physiological roles of insulin in the brain. As pointed out by Collingridge et al. and reinforced by the work of Kimura and colleagues (Kimura et al. 2014) many of the molecules linked to the pathogenesis of AD are components of the NMDA receptor-LTD cascade. These associations do beg the question whether the relationship between diabetes and AD is originates from modulation of hippocampal synaptic plasticity.

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Conclusion Diabetes is one of the few environmental risk factors known for AD and insulin resistance is seen in the AD brain. A simple linear relationship has been proposed whereby insulin resistance leads to a downregulation of AKT activity, releasing inhibition of GSK3β to hyperphosphorylate tau, with AD referred to as Btype 3 diabetes^ (Steen et al. 2005). Despite supporting evidence for this hypothesis the majority of studies probably favor an upregulation of AKT activity in AD (O’Neill et al. 2012). This latter scenario appears at odds with GSK3β being the major tau kinase. Indeed some studies have concluded that the relationship between insulin signaling and AD is independent of GSK3β (Meske et al. 2008; Talbot et al. 2012) while others have suggested the direction of causation between T2D and AD may be reversed (Janson et al. 2004) or even that these two commonly occurring diseases are not mechanistically linked at all (Murakami et al. 2011). However, with the limited success of Aβ-clearing therapies in clinical trials suggesting that alternative or adjunctive treatments will be required for AD, clarifying how diabetes infers risk is a pressing issue. In this respect the ongoing trials of intranasal insulin will be informative (Freiherr et al. 2013) (and reviewed by (Biessels and Reagan 2015)) but the onus is also on researchers in this field to devise improved experimental paradigms. Animal models of neuropsychiatric diseases, including AD, are improving all the time but there remains concern over the translatability of positive results to human clinical trials. This is likely to reflect a greater disparity, compared to other organs, between the human and rodent brains. Studies performed on post mortem brain tissue are contextually accurate but inherently retrospective and it is difficult to ascertain whether differences seen in casecontrols comparisons represent the ‘cause’ or ‘effect’ of the disease process. A case-control experiment using post mortem brain tissue would ideally target regions with the most susceptible cells but these neurons are lost prior to autopsy. One alternative experimental paradigm is to employ belatedly affected areas of the AD brain as surrogates for those severely affected areas many years earlier in the disease course (Sutherland et al. 2011a). The development of patientderived neurons also holds great promise for a ‘humanized’ model for teasing out aspects of AD pathogenesis (Ooi et al. 2013). GSK3β has already identified as a major factor differentiating AD cell lines from those derived from controls (Israel et al. 2012). Lastly it is always worth re-considering our current understanding of the pathogenesis of sporadic AD. The amyloid cascade hypothesis has stood the test of time and it continues to be reinforced by the latest genetic (Jonsson et al. 2012) and imaging studies (Cohen and Klunk 2014). Indeed in their review, Cohen and Klunk point out, that with the move towards clinical trials with asymptomatic individuals means it is

critical to identify the earliest changes in amyloid deposition and their significance. At present Aβ is largely regarded as a degradation product, a notion that should allow it to be targeted with impunity, even early in AD. However, there is also mounting evidence that Aβ plays a physiological role in modulating synaptic plasticity (Pearson and Peers 2006; Parihar and Brewer 2010), and that these effects are opposite to those of insulin. As we strive for earlier diagnosis and implementation of therapies in AD, treatments directed at Aβ could become a more delicate balancing act. Perhaps, more importantly, entertaining the possibility that Aβ has physiological role could be paradigm shift that propels researchers to explore previously ignored possibilities for how risk factors such as diabetes fit into the complex pathogenesis of AD.

Acknowledgments The authors would firstly likely to thank the brain donors and their families whose kind donation provides the impetus for our research. The authors also thank A/Prof Paul Witting and Prof. Jillian Kril for their support and discussions on the content of this manuscript. We acknowledge the kind support of the Judith Jane Mason and Harold Stannett Williams Memorial Foundation.

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The rise and fall of insulin signaling in Alzheimer's disease.

The prevalence of both diabetes and Alzheimer's disease (AD) are reaching epidemic proportions worldwide. Alarmingly, diabetes is also a risk factor f...
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