CHOLESTEROL AND NEURONAL SUSCEPTIBILITY TO BETA-AMYLOID TOXICITY.

NIH Public Access Author Manuscript Cogn Sci (Hauppauge). Author manuscript; available in PMC 2014 October 20.

NIH-PA Author Manuscript

Published in final edited form as: Cogn Sci (Hauppauge). 2010 July 1; 5(1): 35–56.

CHOLESTEROL AND NEURONAL SUSCEPTIBILITY TO BETAAMYLOID TOXICITY Alexandra M. Nicholson and Adriana Ferreira* Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Abstract


Alzheimer’s disease (AD) is a devastating neurocognitive disorder rapidly growing across the elderly population. Although few cases arise due to genetic mutations, sporadic AD is the most common form of this disease. Therefore, there is a continuing research effort to discover a unifying cause of this form of AD. To date, the only strong genetic correlate to the sporadic AD is inheritance of the apolipoprotein E4 (ApoE4) allele, whose encoded protein is involved in cholesterol transport in the central nervous system. This genetic link has prompted a series of studies on the potential molecular mechanisms by which cholesterol could modulate neuronal degeneration in the context of AD. In this review, we discussed the involvement of cholesterol in the production of the pathological hallmarks of the disease and how it might alter the susceptibility of cells to AD-related insult. Finally, we discussed the use of cholesterol-lowering drugs as a potential preventative approach in AD.

Keywords Cholesterol; Alzheimer’s disease; beta-amyloid; statins

Introduction NIH-PA Author Manuscript

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, language deficits, and space and time disorientation, among other neuropsychiatric symptoms (reviewed by Collie and Maruff, 2000). Since its discovery by Alois Alzheimer in 1901, AD has continually been of scientific interest due to its increasing effect among the elderly population. As a result, the morphological hallmarks of this neurodegenerative disorder, amyloid plaques and neurofibrillary tangles (NFTs), have been extensively studied. These lesions consist of extracellular deposits of the beta-amyloid (Aβ) peptide and intracellular accumulation of hyperphosphoylated forms of the microtubuleassociated protein tau, respectively (Glenner and Wong, 1984; Kosik et al., 1986; Wood et al., 1986). Though the multifaceted nature of AD has made it difficult to distinguish whether these pathological hallmarks initiate or are a consequence of the disease, understanding how

*

Correspondence should be addressed to: Adriana Ferreira, M.D., Ph. D., Cell and Molecular Biology Department Northwestern University, Ward Building 8-140, 303 East Chicago Avenue, Chicago, Illinois 60611, Phone: (312) 503-0597, Fax: (312) 503-7345, [email protected].

Nicholson and Ferreira

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these aggregates originate has been and remains a question on the forefront of AD research. A growing body of evidence suggests that the accumulation of Aβ peptides, formed by βand γ-secretase digestion of the amyloid precursor protein (APP), induces tau hyperphosphorylation and proteolysis leading to the formation of NFT (Vassar et al., 1999; Chung et al., 2001; Gamblin et al., 2003; reviewed by Tsai et al., 2004; Takashima, 2006). Unfortunately, researchers have been unsuccessful in developing pharmacological or therapeutic interventions that can halt the progression of protein dysfunction in AD. Therefore, it is becoming more critical to minimize the risk of developing the disease in an attempt to avoid its onset.


Cholesterol has gained interest as a potential risk factor for AD as a result of numerous studies. Early reports suggested a link between cardiovascular diseases and a risk of developing AD (Sparks et al., 1990; Kokmen et al., 1991; Sparks et al., 1993; Hofman et al., 1997). More recently, a population-based study demonstrated that high cholesterol levels represent a significant risk factor for AD (Kivipelto et al., 2001; Solomon et al., 2009). A relationship between moderately elevated cholesterol levels in midlife and increase incidence of AD and vascular dementia 3 decades later was also established in a large (9,844 participants) and diverse cohort (Solomon et al., 2009). Additionally, inheritance of the apolipoprotein E4 (ApoE4) allele, the transcript for a protein involved in cholesterol transport in the central nervous system (CNS), increases the probability one will develop AD (Corder et al., 1993). The picture emerging from these studies strongly suggests that cholesterol could play a role in the pathobiology of this disease. In this review, we discussed the potential role of cholesterol, including how it might be involved in the development of the pathological hallmarks of AD as well as how it might directly or indirectly intensify their mechanisms of neurotoxicity on a cellular level. Finally, we give an overview of the controversy behind cholesterol-lowering drugs and their potential to decrease one’s risk of developing AD.

Cholesterol production in the brain


Cholesterol constitutes a major component of the myelin sheath in the nervous system (reviewed by Dietschy, 2009). However, neurons of the hippocampus, the brain area primarily affected by AD pathology, are not myelinated (Andersen, 1960; Raastad and Shepherd, 2003). In non-myelinated cells, most of the cholesterol resides primarily in the plasma membrane where it is organized into specific membrane microdomains known as lipid rafts. These specific membrane compartments are involved in cellular processes, protein sorting, signaling complex formation, and the initiation of several signal transduction pathways (reviewed by Simons and Ikonen, 1997; Brown and London, 1998; Simons and Ikonen, 2000; Simons and Toomre, 2000; Ikonen, 2001; Suzuki, 2002). Cholesterol determines the proper cellular membrane fluidity, membrane protein components and their organization into lipid rafts, and is a critical precursor or cofactor for other signaling molecules. Therefore, the maintenance of proper cholesterol synthesis, transport, and intracellular sorting is tightly regulated. Most mammalian cells can synthesize cholesterol according to their own requirement, with acetate being the starting substrate. In cells outside of the CNS, most cholesterol originates either by de novo synthesis or from exogenously supplied lipoproteins secreted by the liver (Spady and Dietschy, 1983; Dietschy et al., 1993).

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Since brain cholesterol levels are five to ten times higher than those in other organs and cholesterol turnover in the brain is 6 times slower than in other tissues, it is not surprising that cholesterol homeostasis in brain cells is distinct from other cell types (Bjorkhem et al., 1997; reviewed by Dietschy and Turley, 2004). To date, there is solid evidence that the majority of cholesterol in the CNS is synthesized locally rather than imported from blood lipoproteins (Dietschy et al., 1983; Edmond et al., 1991; Jurevics and Morell, 1995; Osono et al., 1995; Turley et al., 1998). Central neurons express 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the enzyme required in the cholesterol synthesis pathway (Volpe and Hennessy, 1977; Swanson et al., 1988). Furthermore, cholesterol synthesis has been detected in both embryonic and postnatal neuron cultures (Lopes-Cardozo et al., 1986; Saito et al., 1987; Tabernero et al., 1993). However, it has been questioned whether the amount of HMG-CoA reductase is enough to establish the necessary levels of cholesterol, as well as other HMG-CoA reductase-dependent molecules, as neurons develop. This question is in agreement with multiple reports suggesting that neurons require glial-derived cholesterol for growth and survival (Ignatius et al., 1986; Handelmann et al., 1992; Poirier et al., 1993; Meyer-Franke et al., 1995; Mauch et al., 2001; reviewed by Goritz et al., 2002; Pfrieger, 2003b, 2003a). Glial cholesterol, obtained either by de novo synthesis or by recycling cholesterol that has been released from degenerating nerve terminals, complexes with lipidcarrying molecules to produce cholesterol-containing low density lipoprotein (LDL) particles which are secreted by glial cells (Shanmugaratnam et al., 1997). One of the most abundant of these lipid carriers is the glia-derived ApoE (Elshourbagy et al., 1985). ApoE proteins are involved in the transport and distribution of cholesterol and other lipids, particularly to and from neuronal subcellular compartments (reviewed by Mahley, 1988; Poirier, 1994; Herz and Beffert, 2000). On the surface of neuronal cells, ApoE-containing lipoproteins are ligands primarily for the LDL family of cell surface receptors, which are then internalized and broken down within the cell to free the cholesterol from its associated lipoprotein complex (Rebeck et al., 1993; Bu et al., 1994).

ApoE4 in cholesterol homeostasis and AD pathogenesis


Sporadic AD, unlike the familial form, is the most common form of the disease and lacks genetic mutations as a primary cause. However, there is one gene mapped to chromosome 19 that has been implicated as a significant risk factor for both forms of AD (Pericak-Vance et al., 1991). This gene encodes the ApoE protein mentioned above as critical for CNS cholesterol homeostasis. This lipid carrier is polymorphic with three alleles encoding different isoforms: ApoE2, ApoE3, and ApoE4, which differ only in their amino acid residues at positions 112 and 158 (reviewed by Mahley, 1988). Though ApoE3 is most abundantly expressed, it remains inconclusive whether this isoform might be involved in AD pathogenesis. Interestingly, ApoE2, whose allelic frequency is the lowest of the three isoforms in the United States population, seems to have potential neuroprotective qualities that actually may reduce the risk of acquiring AD (Corder et al., 1994; Lippa et al., 1997; Lee et al., 2002). Conversely, the ApoE4 polymorphism was identified as an important factor to the etiology of many AD cases (Corder et al., 1993). This study examined the ApoE genotype profile of individuals from over 40 families and assessed the proportion of AD-affected individuals with each genotype. Their results established that only 20% of



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individuals containing either the ApoE2/3 or ApoE3/3 genotype had AD. Forty-seven percent of people with one ApoE4 allele were affected with AD, while approximately 90% of individuals carrying two ApoE4 alleles had been pathologically diagnosed with this disease. Not only did the number of inherited ApoE4 alleles correlate with an increased risk of developing the disease, but also with a decrease in the average age of onset (Corder et al., 1993).


The data reviewed above suggested that ApoE isoforms might differentially contribute to the pathobiology of AD on a cellular level, though the mechanism of this correlation is not completely understood. Studies have shown that the ApoE4 isoform has a greater binding affinity for LDL receptors than the other ApoE isoforms (Dong et al., 1994; Dong and Weisgraber, 1996). Furthermore, ApoE4 was the least potent isoform to promote cholesterol efflux from both cortical neurons and glial cells (Michikawa et al., 2000). As a result of these findings, research efforts assessed to what extent ApoE4 might promote an increase in neuron cholesterol levels, rendering them more susceptible to either the production or the toxicity induced by the proteinaceous deposits typical in AD. Evidence has emerged suggesting that ApoE does, indeed, regulate cholesterol levels in the synaptic plasma membranes (SPM) (Igbavboa et al., 1997). In a study conducted in 2002, Hayashi and colleagues utilized ApoE4 knock-in mice to determine cholesterol content in the SPMs isolated from these transgenic mice, as well as in ApoE3-overexpressing and wild type mice. Unlike ApoE3 and wild type mice, animals overexpressing ApoE4 had increased cholesterol in the exofacial leaflet of SPMs at 8 weeks of age (Hayashi et al., 2002). Although these results provided evidence that ApoE4 might be linked to AD in a cholesterol-dependent manner, the effects of ApoE overexpression are vast and will require more analyses to elucidate which ApoE4-induced cellular modifications primarily contribute to AD onset and pathology.

Cholesterol and Aβ production


One of the early steps in the pathobiology of AD is the increase in Aβ levels (reviewed by Bharadwaj et al., 2009). The production of this toxic peptide is the result of the amyloidogenic secretase cleavage of the APP transmembrane protein. To initiate Aβ formation, APP is first cleaved by β-secretase, an enzyme more commonly known as β-site APP cleaving enzyme or BACE-1 (Urmoneit et al., 1995; Vassar et al., 1999). As a result of this cleavage event, the extracellular portion of APP is released in a soluble form, APPsβ. The remaining portion of the APP molecule within the membrane is further cleaved at the Cterminal end of Aβ by γ-secretase to yield the Aβ protein primarily of 40–42 amino acids (Anderson et al., 1992; Haass et al., 1992; Roher et al., 1993; Xia et al., 1997). Alternatively, APP undergoing non-amyloidogenic processing is cleaved first by the enzyme α-secretase followed by γ-secretase. The α-secretase cleavage event initiates the release a different soluble portion of APP than that of β-secretase APP cleavage, APPsα. Furthermore, APP cleavage by α-secretase is considered non-amyloidogenic APP processing because the α-secretase cleavage site is within the Aβ portion of APP (Sisodia et al., 1990). Thus, factors that favor either α- or β-secretase APP proteolysis could decrease or increase the Aβ burden, respectively.



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Cholesterol seems to be one of those factors. Earlier reports showed that cholesterol-linked cardiovascular diseases, such as coronary artery disease, were associated with Aβ deposition in the brain similar to that of AD patients (Sparks et al., 1990; Sparks et al., 1993). However, it was not until 1994 when the first experimental evidence suggesting interplay between cholesterol consumption and Aβ formation in the brain was published. In this study, rabbits were fed either a control or a hypercholesterol diet for up to 8 weeks before they were sacrificed and their brains analyzed. Rabbits on the hypercholesterol diet had significantly elevated plasma cholesterol levels as well as clinical signs of jaundice and renal failure; most likely do to fatty liver and fatty deposits in their arteries. Interestingly, a timedependent increase in Aβ immunoreactivity was detected in the hippocampus and cortex of rabbits on the hypercholesterol diet (Sparks et al., 1994). Similar observations have since been obtained in transgenic mouse models of AD (Howland et al., 1998; Refolo et al., 2000; Shie et al., 2002).


Although a debate remains as to whether plasma cholesterol might affect levels of this sterol in the brain, these findings provided significant evidence that cholesterol might be linked to Aβ production and deposition. Further support for such a role was obtained by manipulating membrane cholesterol in different cell types to determine to what extent Aβ production, or that of similar proteins, is altered. For example, increasing membrane cholesterol by means of incubations with cholesterol solubilized in either a methyl-β-cyclodextrin (MBCD) complex or by ethanol in APP-transfected HEK293 cells decreased the amount of APPsα secreted (Bodovitz and Klein, 1996). Similar results were obtained using a different approach to increase cellular cholesterol content in COS-1 cells. In these experiments, COS-1 cells were exposed to various forms of LDL containing non-esterified cholesterol. While the dose of cholesterol-containing LDL complexes correlated with an increase in membrane cholesterol content in these cells, a subsequent negative correlation in APPsα release was observed (Racchi et al., 1997).


Both of these studies suggested that increased membrane cholesterol may attenuate αsecretase processing of APP, though neither provided evidence of the converse: that decreasing membrane cholesterol increases α-secretase activity. This information arose when research efforts assessed α-secretase activity in response to decreased membrane cholesterol in both neuronal and non-neuronal cell lines. In these experiments, membrane cholesterol was removed from cellular membranes using MBCD, a glycoprotein able to encapsulate cholesterol to render it water-soluble. Cells in which cholesterol had been reduced by MBCD showed a marked increase in secreted APPsα (Kojro et al., 2001). Additionally, decreased cholesterol actually reduced the amount of Aβ peptides generated in these cellular models. These data supported previous findings in cultured hippocampal neurons (Simons et al., 1998). Taken together, these results provided insights into the role of cellular cholesterol levels and the regulation of the enzymes involved in APP processing leading to Aβ production in the context of AD.

Cholesterol might mediate Aβ-membrane interactions Not only is the process of Aβ production a toxic factor in AD pathogenesis, but also the effect that Aβ has on neuronal cells after it has been released into the extracellular space.



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Although different hypotheses remain as to how exogenous Aβ exerts its neurotoxic effects, most suggest the interaction of Aβ with surrounding cellular membranes. In fact, using electron microscopy techniques, Aβ has been shown to associate with cell surface plasma membranes in the brains of AD patients (Yamaguchi et al., 2000). Similar findings were reported in aged dogs, since dogs are a species of vertebrates that demonstrate agedependent cognitive decline correlated with Aβ accumulation (Torp et al., 2000). Aβ has also been shown to exert membrane-disordering properties, both in cellular and artificial membranes, further supporting an interaction between this peptide and membrane structures. Several reports have provided evidence of Aβ binding to cholesterol-rich low-density areas of membranes (Morishima-Kawashima and Ihara, 1998; Mizuno et al., 1999; Oshima et al., 2001; Kawarabayashi et al., 2004). One of the first biochemical assessments of Aβ-lipid interaction was conducted by Avdulov et al. (1997). This research group discovered a preferential interaction of Aβ with cholesterol over other lipids of the membrane bilayer using in vitro techniques (Avdulov et al., 1997). Later evidence was obtained of Aβ binding to other components of the membrane, such as ganglioside-M1 (GM1). Interestingly, the amount of GM1 necessary for Aβ binding was decreased when cholesterol was present, an environment mimicking that of actual lipid rafts (Matsuzaki and Horikiri, 1999). Data challenging the enhanced effects of cholesterol on Aβ-membrane interactions have also been reported. For example, membrane cholesterol in synthetic membranes actually excluded Aβ peptide from the membrane, most likely due to rigidifying nature of membrane cholesterol (Curtain et al., 2003). These results were in agreement with a study done in 2006 in which the addition of cholesterol to synthetic membranes reduced the insertion of Aβ25–35 (Dante et al., 2006). These conflicting results on the role of cholesterol in Aβ-membrane interactions could be due to the model system in which these questions were addressed. Regardless, it is difficult to dispute that cholesterol might, at least in part, mediate the ability of Aβ to interact with its surrounding cellular membranes.

Cholesterol and Aβ toxicity


The in vitro models of cellular membranes used in the experiments described above provided useful data regarding the role of cholesterol as a modulator of Aβ-membrane interactions. However, they did not address to what extent cholesterol might alter the susceptibility of cells to Aβ toxicity at a cellular level in the context of AD. It is known that Aβ exerts its neurotoxic effects, at least in part, by enhancing calcium (Ca2+) influx (reviewed by Ingram, 2005; Smith et al., 2005; Mattson, 2007; Bojarski et al., 2008; Green and LaFerla, 2008). Interestingly, cholesterol has been implicated in the susceptibility of cells to Ca2+ influx (Bastiaanse et al., 1994). Cholesterol appeared to be protective against Aβ-induced Ca2+ influx both in dissociated mouse brain cells and in human lymphocytes and immortalized hypothalamic neurons (Hartmann et al., 1994; Kawahara and Kuroda, 2001). This seems not to be the case in mature hippocampal cultures. In this report, elevated membrane cholesterol actually increased the susceptibility of cells to Aβ-induced elevation in Ca2+ influx leading to cell death via a tau-dependent mechanism (Nicholson and Ferreira, 2009). Thus, the effects of cholesterol on Ca2+ influx induced by Aβ might vary in different cell types and, more importantly, in different stages of neuronal maturation.



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Another mechanism through which Aβ is thought to cause neurotoxicity is by means of inducing abnormal posttranslational processing of the tau protein. Of these posttranslational modifications, Aβ-induced tau hyperphosphorylation has been most extensively studied due to its hypothesized role in tau aggregation and NFT formation in AD (reviewed by Lee, 1996; Michaelis et al., 2002; Chun and Johnson, 2007; Iqbal et al., 2009). However, recent research efforts have also shown that Aβ-induced cleavage of tau can not only accelerate tau aggregation, but can generate tau fragments that are neurotoxic themselves (Chung et al., 2001; Gamblin et al., 2003; Park and Ferreira, 2005; Park et al., 2007). The suspicion that cholesterol might be a factor in AD tau pathology arose in studies conducted in models of Niemann-Pick type C (NPC) disease. Patients with this disease show disruption in several cellular transport processes leading to the accumulation of cholesterol and glycolipids in lysosomal compartments. Interestingly, tau tangle pathology is found in the brains of NPC patients, with or without other AD histopathological changes (Auer et al., 1995; Love et al., 1995; Suzuki et al., 1995). One of the first reports suggesting a link between cholesterol and tau pathology on a cellular level determined that cellular cholesterol deficiency in primary cortical neurons induced tau phosphorylation in culture (Fan et al., 2001). Unfortunately, little is known regarding how cholesterol might be a factor in these cellular processes in the specific context of AD. Transgenic models of AD have been a useful tool in the beginning stages of understanding the relationship of many factors involved in this disease. Thus, phosphorylated tau has been detected to accumulate in cholesterol-rich portions of cellular membranes in mice overexpressing APP (Kawarabayashi et al., 2004). However, it remains unknown whether cholesterol was a direct mediator of these observations. In addition, when neuron cholesterol content was increased in transgenic mice fed hypercholesterol diets, enhanced tau kinase activation and subsequent tau phosphorylation were detected as compared to controls (Ghribi et al., 2006). A positive correlation between cholesterol content and tau toxicity was also established in primary hippocampal neurons in culture. When membrane cholesterol content in these cells was increased, either by the natural effect of aging or pharmacologically, their susceptibility to Aβ-induced calpain-mediated cleavage of tau into a neurotoxic fragment was significantly enhanced (Nicholson and Ferreira, 2009). Furthermore, the reciprocal was true in which decreasing membrane cholesterol content in hippocampal neurons attenuated tau cleavage induced by Aβ (Nicholson and Ferreira, 2009). Taken together, these results suggest that cellular cholesterol levels might be involved in the molecular mechanisms that underlie Aβ-induced excytotoxicity and tau posttranslational modifications.

Cholesterol-lowering drugs: a possibility for AD prevention? The data reviewed above strongly suggest a potential involvement of cholesterol in AD pathology. These findings raise the question as to whether cholesterol-lowering drugs might be beneficial for AD prevention and/or treatment. Although no drugs currently exist to specifically target cholesterol in the brain, statins have been commonly used to decrease peripheral cholesterol levels. Statins are a class of drugs that inhibit HMG-CoA reductase, prevent the formation and entry of LDL cholesterol into the circulation, and upregulate LDL receptor activity (Mabuchi et al., 1981; Bilheimer et al., 1983; Mabuchi et al., 1983). To what extent changes in peripheral cholesterol levels affect brain cholesterol is an open



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question. Regardless, longitudinal and case studies have been conducted to assess whether HMG-CoA reductase inhibitors might affect one’s risk of AD and its hallmark pathology (Jick et al., 2000; Wolozin et al., 2000; Scott and Laake, 2001; Tokuda et al., 2001; Buxbaum et al., 2002; Hajjar et al., 2002; Rockwood et al., 2002). Some AD clinical trials suggest that the use of statins could reduce the incidence of AD. Thus, preliminary results from the AD cholesterol lowering treatment trial showed the benefits of atorvastatin in cognitive function, clinical efficacy, and psychiatric symptoms after taking the drug for 12 months (Sparks et al., 2005). A decrease in the overall risk of developing AD and related dementias was also observed when individuals of 50 years and older were prescribed simvastatin, pravastatin, fluvastatin, lovostatin, or cerivastain (Jick et al., 2000; Wolozin et al., 2000; Buxbaum et al., 2002; Hajjar et al., 2002). Other clinical reports question a link between the use of these cholesterol-lowering drugs and AD (Scott and Laake, 200; Rockwood et al., 2002). These conflicting clinical outcomes might be due to the plieotropic nature of HMG-CoA reductase inhibitors, due to the requirement of this enzyme in the synthesis of other cellular molecules. Nor can it can be ruled out that the beneficial effects of statins could be independent of potential changes in brain cholesterol levels since these drugs also have anti-inflamatory, antioxidative, antithrombogenic, and immunological effects. In sum, even after extensive epidemiological, cellular, and biochemical investigations into the involvement of cholesterol in AD pathophysiology, its exact role in this disease remains obscure. Nevertheless, further investigation into the correlation between cholesterol and AD pathology could identify new targets for therapeutic intervention for the prevention and or treatment of this devastating disease.

Acknowledgments Supported by NIH grant RO1 NS39080 and Alzheimer’s Association grant 57869 to A.F.

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Individual susceptibility to toxicity.

[Cholesterol, neuronal activity and Alzheimer disease].

Chronic activation of FXR in transgenic mice caused perinatal toxicity and sensitized mice to cholesterol toxicity.

Membrane Cholesterol Modulates Superwarfarin Toxicity.

Influences of the circadian clock on neuronal susceptibility to excitotoxicity.

Astrocytic phospholipase A2 contributes to neuronal glutamate toxicity.

Microfluidics for Antibiotic Susceptibility and Toxicity Testing.

Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity.

Genetic Aspects of Susceptibility to Mercury Toxicity: An Overview.

Postnatal mice have low susceptibility to paracetamol toxicity.

Increased susceptibility to lead toxicity in rats fed semipurified diets.

Klebsiella capsular type K7 in relation to toxicity, susceptibility to phagocytosis and resistance to serum.

Non-neuronal cholinergic system in airways and lung cancer susceptibility.

Neuronal substrates underlying stress resilience and susceptibility in rats.

Growth factors and vitamin E modify neuronal glutamate toxicity.

Plasma fibrinogen is a natural deterrent to amyloid beta-induced platelet activation and neuronal toxicity.

Prion infection impairs cholesterol metabolism in neuronal cells.

The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

Temperature and species differences in susceptibility of kidney cell cultures to mercury toxicity.

Inhibition of LtxA toxicity by blocking cholesterol binding with peptides.

Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-β-cyclodextrine is prestin-dependent.

Influence of the cholesterol content of mammalian spermatozoa on susceptibility to cold-shock.

Antioxidants inhibit neuronal toxicity in Parkinson's disease-linked LRRK2.

Zinc Modulates Nanosilver-Induced Toxicity in Primary Neuronal Cultures.