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Researchers Probe the Aging Brain in Health and Disease M. J. Friedrich

S

an Diego—“By the time you’re 80 years old, you’ve learned everything. You only have to remember it,” quipped comedian George Burns at various points throughout his lengthy career. Holding on to memories with age is fundamental to one’s sense of well-being. But although aging is a risk factor for dementias that bring about serious and disabling memory decline, a good portion of older adults remain sharp and quick-witted into their 90s and beyond, experiencing perhaps only minor or annoying alterations in memory and cognitive function. So what distinguishes a healthy aging brain from one in the grips of a dementing illness? Researchers at the annual 2013 Society for Neuroscience meeting held here in November presented insights into how the brain ages normally across a life span and how those alterations compare with changes that occur in brains affected by injury or neurodegeneration.

Scientists are exploring how changes that normally occur in the aging brain compare with those occurring in brains affected by Alzheimer disease and other types of neurodegeneration.

Background photo: Thomas Deerinck/NCMIR/www.sciencesource.com

Memory in the Healthy Aging Brain Carol Barnes, PhD, professor of psychology and neurology at the University of Arizona, Tucson, studies how memory processes change with normal aging across various species, particularly in rats and nonhuman primates. As she noted, animals don’t develop Alzheimer disease (AD) in the course of aging: only humans do. Therefore, animal models can provide an understanding of the functional changes that occur in normal age-related memory loss, as well as those aspects of brain function that are maintained during aging. “Understanding the neurobiological changes in the brain during normative aging is important in its own right, but it also provides a backdrop for understanding dis-

ease processes that can be superimposed on these normative age-related changes,” said Barnes. By separating pathological from normal aging, she and her colleagues are searching for ways to optimize cognitive performance in both healthy individuals and those with neurodegenerative disease. Barnes’ research has focused on the hippocampus—the region linked to spatial learning and memory—in rats and nonhuman primates. All animal models tested show changes as they age on memory tasks that depend on the hippocampus for good performance, suggesting that this brain structure is vulnerable to the aging process. Her laboratory and others have also observed

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similar changes across species in tasks that depend on the perirhinal cortex for memory. A critical issue in the study of normal aging is what happens to the brain networks underlying memory. For many years, agerelated memory problems were attributed to neuronal loss, but this disturbing picture of the aging brain has turned out to be false, said Barnes. “The good news is that in normal aging, not only do we keep a relatively steady number of neurons in the hippocampus and in the perirhinal cortex, but the functional properties of cells in these regions are well preserved,” she said. But if cell loss is not at fault, what does go wrong in the aging brain? Research points tochangesintheconnectionsbetweencells— alterations in synaptic connectivity that diminish the communication between cells. In some cases an anatomical change occurs, with the number of synaptic contacts declining. In other situations the number of synapses may remain steady while the ability of the synapses to be modified—the socalled plasticity of the synapse—is altered. If the cells do not communicate well, synaptic plasticity and the ability of the circuits to store information will be impaired, said Barnes.

Tracking Declining Networks Totrackchangesinneuralnetworksinliveanimals, Barnes and her team used ensemble recording methods to record activity from multiple single cells simultaneously. In this way, they examined how certain cells within the hippocampus in rats construct a “cognitive map” when the animal is exploring its surroundings. They found that when a young rat returns to an environment, it almost always retrieves the correct map, in contrast to older rats, which retrieve the wrong map about a third of the time, as if they think they are JAMA January 15, 2014 Volume 311, Number 3

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somewhereelse.“Mapretrievalfailuremaybe one reason older organisms can become lost,” noted Barnes. What goes wrong in map retrieval in the older rats involves the cellular plasticity mechanisms, particularly the strength of synaptic connections that underlie learning, continued Barnes. It’s not that the older animals can’t learn—plasticity does occur— but the strength of the synaptic connections declines with age, leading to mistakes with retrieval. Barnes has also monitored cell activity on a broader scale by looking at gene expression changes that occur during behavioral tests. One such gene that researchers have focused on is Arc (activity-regulated cytoplasmic gene), which is necessary for proper synaptic function and memory consolidation. Because Arc expression indicates where activity is occurring in a cell network, it can be used as a marker of cellular activity and can also show when the cells are activated, helping researchers zero in on the circuits in the hippocampus most affected by the normal aging process. By monitoring Arc activity in 3 primary cell groups within the hippocampus—the granule cells of the dentate gyrus and the pyramidal cells of regions CA1 and CA3—in young, middle-aged, and aging rats, the researchers discovered that Arc gene expression in the CA1 and CA3 cell regions remained the same throughout aging, in contrast to the dentate gyrus, in which the number of granule cells engaged during behavior declined with aging. Work in monkeys and in humans also yielded similar results, with older organisms showing reduced activity in the dentate gyrus that also correlated with poorer memory. And additional work in rats indicates that DNA methylation reduces the expression of Arc in the granule cells of the older animals. These findings indicate that the networks targeted in normal aging differ from those known to be targeted in AD, in which CA1cellsareparticularlyvulnerablewhilegranulecellsdonotdegenerateuntilverylateinthe neurodegenerative process, said Barnes. “While normative aging and AD can occur together, they have independent neurological patterns,” said Barnes. “And because hippocampal granule cells are particularly vulnerable in normal aging, they may be a good target for optimizing cognition with age.” 232

ApoE4 Sets Stage for Neuropathology One of the differences between the healthy aging brain and a brain that is vulnerable to neuropathology is the presence of apolipoprotein E4 (ApoE4) (Friedrich MJ. JAMA. 2012;308[24]:2553-2555). “Our working hypothesis over the last several years has been that ApoE4 sets the stage for neuropathology, while a second hit—anything that stresses or injures a neuron—determines the type of neuropathology that will result,” said Robert Mahley, MD, PhD, senior investigator at the Gladstone Institute of Neurological Disease, University of San Francisco, California. ApoE4 is the major genetic risk factor for sporadic AD. It influences AD in at least 2 ways: it raises the risk of developing the disease, and it lowers the age at onset by as much as 16 years. To a lesser but still important degree, ApoE4 is also associated with other neuropathological disorders as well as poor outcomes in traumatic brain injury (Tsuang D et al. JAMA Neurol. 2013;70[2]: 223-228). ApoE4 isn’t rare, as it occurs in about 25% of the population and about 65% to 80% of patients with AD have at least 1 ApoE4 allele, said Mahley. Although ApoE4 interacts with many of the mediators believed to be involved in AD, such as amyloid-β deposits and hyperphosphorylated tau, it also acts independently of these systems and has a direct detrimental effect on neuronal cells. For this reason, said Mahley, a therapeutic approach designed to target ApoE has broad potential in treating not only AD but other neuropathological disorders. ApoE4 is 1 of 3 major isoforms of ApoE; the others are ApoE2 and ApoE3. In the brain, ApoE is normally synthesized by astrocytes to support lipid transport, but it is also produced by neurons in response to insult or injury to promote neuronal repair. The 3 isoforms differ from one another by only a single amino acid, but this seemingly minor difference has profound consequences on the structure and function of the protein and affects ApoE’s ability to promote neuronal health instead of neuronal damage, especially when ApoE synthesis is increased after cell injury, said Mahley. The amino acid difference causes the ApoE4 protein to assume a unique 3D conformation that renders it less stable and more susceptible to proteolytic cleavage than the other isoforms. This cleavage generates neurotoxic fragments that cause mitochondrial dysfunction and cytoskeletal alterations

(Mahley RW and Huang Y. Neuron. 2012; 76[5]:871-885). Because ApoE plays a fundamental role in cellular processes, shutting down its production is not a viable therapeutic approach. More promising avenues include developing structure-correcting agents that convert the aberrant structure of ApoE4 to that of ApoE3, thus preventing the generation of neurotoxic fragments. Proof of principle for this structure-correcting approach has been established for other diseases; compounds for treating cystic fibrosis and other indications are in clinical trials. Mahley and his team have identified several small molecule structural correctors and are testing them in transgenic mouse models that express human ApoE4. In vivo studies of the structural corrector PY101 in these mouse models show a reduction of 20% to 30% in the number of neurotoxic fragments after 10 days of treatment, he said. In addition, preliminary data indicate that treatment with PY-101 can restore learning and memory in the ApoE4 mice to a level similar to that of ApoE3 mice. Structurecorrectormoleculesarenotthe onlytherapeuticapproachesunderstudythat target ApoE4. Mahley noted that his group is alsoworkingondevelopingproteaseinhibitors that prevent ApoE4 from being chopped into dangerous fragments. In other laboratories, preclinicalworkwithApoEmimeticsdesigned to enhance ApoE signaling or ApoE-mediated clearance is showing promise (Vitek MP et al. Neurodegener Dis. 2012;10[1-4]:122-126). And yet another approach involves increasing ApoE levels in the brain with the drug bexarotene (Cramer et al. Science. 2012;335[6075]: 1503-1506). In mouse models of AD, bexarotene was shown to increase the expression of ApoE in the brain, along with other brain proteins, and enhanced clearing of soluble amyloidβwasobserved.Aclinicaltrialisunderway to determine the safety of this approach, with results expected next year. But Mahley cautionedthatincreasingApoE4levelsraisesconcerns because of its neurotoxicity. Although much remains to be learned about how ApoE4 affects the brain, it clearly plays a role in the pathogenesis of many different neurological diseases, said Mahley. Although further testing is needed before therapies targeting ApoE are ready for use in humans, he said, “it’s clear that ApoE4 is a viable target and provides a promising approach for treating AD and other neurological diseases.”

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Researchers probe the aging brain in health and disease.

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