Age-related Cognitive Dysfunction Research Articles

Late-Life Metabolic Dysfunction-Associated Steatotic Liver Disease and its Association With Physical Disability and Dementia.

The burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing rapidly, including among older adults. The number of older adults is also rising with concomitantly increasing rates of age-related physical and cognitive dysfunction. However, data on whether MASLD affects physical and cognitive function in older adults is limited. As such, we aimed to identify whether prevalent MASLD influences the risk of incident physical disability or dementia in initially healthy older adults. A post-hoc analysis of participants from the ASPREE-XT cohort study, which recruited community-dwelling older adults without a history of cardiovascular disease, dementia, or independence-limiting functional impairment. The Fatty Liver Index (to identify MASLD) was calculated in those with complete data. Cox proportional-hazards models were used to investigate the outcomes of dementia and persistent physical disability in participants with MASLD vs those without. Of the 9097 individuals included (mean age 75.1 ± 4.2 years; 45.0% men), 341 (3.7%) developed persistent physical disability and 370 (4.1%) developed dementia over a median follow-up of 6.4 years (IQR 5.3-7.5 years). When adjusting for known contributors including age, gender, education, comorbidity, and functional measures, MASLD was associated with an increased risk of persistent physical disability (HR 1.41 [95% CI: 1.07-1.87]) and reduced risk of incident dementia (HR 0.63 [95% CI: 0.48-0.83]). Prevalent MASLD is associated with reduced rates of incident dementia but increased risk of persistent physical disability in initially relatively healthy older adults. Understanding the mechanisms underlying these divergent results to allow appropriate risk stratification and counseling is important.

Impaired Neurovascular Coupling and Increased Functional Connectivity in the Frontal Cortex Predict Age-Related Cognitive Dysfunction.

Impaired cerebrovascular function contributes to the genesis of age-related cognitive decline. In this study, the hypothesis is tested that impairments in neurovascular coupling (NVC) responses and brain network function predict cognitive dysfunction in older adults. Cerebromicrovascular and working memory function of healthy young (n = 21, 33.2±7.0 years) and aged (n = 30, 75.9±6.9 years) participants are assessed.To determine NVC responses and functional connectivity (FC) during a working memory (n-back) paradigm, oxy- and deoxyhemoglobin concentration changes from the frontal cortex using functional near-infrared spectroscopy are recorded. NVC responses are significantly impaired during the 2-back task in aged participants, while the frontal networks are characterized by higher local and global connection strength, and dynamic FC (p < 0.05). Both impaired NVC and increased FC correlate with age-related decline in accuracy during the 2-back task. These findings suggest that task-related brain states in older adults require stronger functional connections to compensate for the attenuated NVC responses associated with working memory load.

Early cerebral amyloid-β accumulation and hypermetabolism are associated with subtle cognitive deficits before accelerated cerebral atrophy

AimsAlzheimer’s disease (AD) is characterized by the accumulation of amyloid beta (Aβ) in the brain. The deposition of Aβ is believed to initiate a detrimental cascade, including cerebral hypometabolism, accelerated brain atrophy, and cognitive problems—ultimately resulting in AD. However, the timing and causality of the cascade resulting in AD are not yet fully established. Therefore, we examined whether early Aβ accumulation affects cerebral glucose metabolism, atrophy rate, and age-related cognitive decline before the onset of neurodegenerative disease.MethodsParticipants from the Metropolit 1953 Danish Male Birth Cohort underwent brain positron emission tomography (PET) imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) (N = 70) and [18F]Fluorodeoxyglucose (FDG) (N = 76) to assess cerebral Aβ accumulation and glucose metabolism, respectively. The atrophy rate was calculated from anatomical magnetic resonance imaging (MRI) scans conducted presently and 10 years ago. Cognitive decline was examined from neurophysiological tests conducted presently and ten or 5 years ago.ResultsHigher Aβ accumulation in AD-critical brain regions correlated with greater visual memory decline (p = 0.023). Aβ accumulation did not correlate with brain atrophy rates. Increased cerebral glucose metabolism in AD-susceptible regions correlated with worse verbal memory performance (p = 0.040).ConclusionsAβ accumulation in known AD-related areas was associated with subtle cognitive deficits. The association was observed before hypometabolism or accelerated brain atrophy, suggesting that Aβ accumulation is involved early in age-related cognitive dysfunction. The association between hypermetabolism and worse memory performance may be due to early compensatory mechanisms adapting for malfunctioning neurons by increasing metabolism.

Protective effects of apigenin on the brain transcriptome with aging

Brain aging is associated with reduced cognitive function that increases the risk for dementia. Apigenin is a bioactive plant compound that inhibits cellular aging processes and could protect against age-related cognitive dysfunction, but its mechanisms of action in the brain have not been comprehensively studied. We characterized brain transcriptome changes in young and old mice treated with apigenin in drinking water. We observed improved learning/memory in old treated mice, and our transcriptome analyses indicated that differentially expressed genes with aging and apigenin were primarily related to immune responses, inflammation, and cytokine regulation. Moreover, we found that genes/transcripts that were increased in old vs. young mice but downregulated with apigenin treatment in old animals were associated with immune activation/inflammation, whereas transcripts that were reduced with aging but increased with apigenin were related neuronal function and signaling. We also found that these transcriptome differences with aging and apigenin treatment were driven in part by glial cells. To follow up on these in vivo transcriptome findings, we studied aged astrocytes in vitro, and we found that apigenin reduced markers of inflammation and cellular senescence in these cells. Collectively, our data suggest that apigenin may protect against age-related cognitive dysfunction by suppressing neuro-inflammatory processes.

Red Cabbage Anthocyanins Attenuate Cognitive Impairment By Attenuating Neuroinflammation and Regulating Gut Microbiota in Aging Mice.

Red cabbage anthocyanins may provide health benefits that may be associated with antiaging. The protection of red cabbage anthocyanin-rich extract (ARE) and cyanidin-3-diglucoside-5-glucoside-rich extract (CY3D5G) against age-related cognitive dysfunction was investigated in normal aging mice (male C57BL/6J, 12 months old) administered orally for 12 weeks. Behavioral tests showed that ARE and CY3D5G significantly decreased cognitive impairment (p < 0.05) and had no effect on motor disorder. ARE and CY3D5G increased superoxide dismutase activity by 29.18 and 23.09% and decreased malondialdehyde by 15.74 and 10.05%, respectively, compared to the control. Histological staining showed that ARE and CY3D5G treatment reduced hippocampal neuronal damage and brain-derived neurotrophic factor degeneration. ARE and CY3D5G significantly reduced IL-1β and IL-6 levels in serum and brain (p < 0.05) by promoting the MAPK signaling pathway while enriching the abundance of butyrate-producing bacteria and altering the functional profile of the microbial community. In conclusion, ARE and CY3D5G may attenuate age-related cognitive dysfunction by reducing neuroinflammation and regulating the gut-brain axis.

Core mechanism and therapeutic methods of aging revealed by Qi-collateral theory in traditional Chinese medicine

Abstract Aging, a complex and multisystem process, has increasingly become a hot issue of global concern. Traditional Chinese medicine has accumulated rich understanding of aging during thousands of years of development, which provides valuable references for the in-depth study of overall aging. According to the Qi-collateral theory in traditional Chinese medicine, essence is the origin of life; Qi is the driving force of life; and spirit is the embodiment of life. This theory interprets key scientific issues such as the formation of life, the driving force of life, the function of Zang-Fu organs, and the spirit and consciousness. Furthermore, it reveals the key mechanism of aging. That is, the deficiency of kidney essence is the root of aging; the loss of vitality is the key of aging; and the depletion of body and spirit is the manifestation of aging. Based on the experience of medical practitioners in the past dynasties, such as nourishing essence, black food tonifying the kidney, and supplementing essence with flesh-blood products, the treatment method of invigorating kidney and supplementing essence, harmonizing Yin and Yang, reinforcing the vitality, and nourishing the body and spirit was proposed. Furthermore, an innovative Chinese patent medicine, Bazi Bushen capsules, is developed, which exerts the antiaging effect by replenishing Qi, invigorating the spirit, and nourishing the body and spirit. Pharmacological and clinical studies have confirmed that this preparation has antiaging effects and are effective in the prevention and treatment of age-related diseases. Experimental studies have shown that Bazi Bushen capsules can delay the overall aging, reduce the DNA methylation and extend the healthy life of naturally aging mice, mitigate the age-related cognitive dysfunction, improve neurological function, maintain redox homeostasis and telomere integrity, and inhibit apoptosis. Moreover, Bazi Bushen capsules can increase the dermal thickness and the collagen fiber and elastic fiber content to prevent skin aging. In addition, Bazi Bushen capsules can correct the lipid metabolism disorders and ameliorate multisystem age-related diseases such as osteoporosis in surgically induced menopausal rats. This article discusses the pathogenesis, treatment, and prescription of aging and the antiaging theory, aiming to provide a basis for delaying aging and preventing related diseases.

Genetic Ablation of Dentate Hilar Somatostatin-Positive GABAergic Interneurons is Sufficient to Induce Cognitive Impairment.

Aging is often associated with a decline in cognitive function. A reduction in the number of somatostatin-positive (SOM+) interneurons in the dentate gyrus (DG) has been described in cognitively impaired but not in unimpaired aged rodents. However, it remains unclear whether the reduction in SOM + interneurons in the DG hilus is causal for age-related cognitive dysfunction. We hypothesized that hilar SOM+ interneurons play an essential role in maintaining cognitive function and that a reduction in the number of hilar SOM + interneurons might be sufficient to induce cognitive dysfunction. Hilar SOM+ interneurons were ablated by expressing a diphtheria toxin transgene specifically in these interneurons, which resulted in a reduction in the number of SOM+ /GAD-67+ neurons and dendritic spine density in the DG. C-fos and Iba-1 immunostainings were increased in DG and CA3, but not CA1, and BDNF protein expression in the hippocampus was decreased. Behavioral testing showed a reduced recognition index in the novel object recognition test, decreased alternations in the Y maze test, and longer latencies and path lengths in the learning and reversal learning phases of the Morris water maze. Our results show that partial genetic ablation of SOM+ hilar interneurons is sufficient to increase activity in DG and CA3, as has been described to occur with aging and to induce an impairment of learning and memory functions. Thus, partial ablation of hilar SOM + interneurons may be a significant contributing factor to age-related cognitive dysfunction. These mice may also be useful as a cellularly defined model of hippocampal aging.

Comparative neurogenetics of dog behavior complements efforts towards human neuropsychiatric genetics.

Domestic dogs display a wide array of heritable behaviors that have intermediate genetic complexity thanks to a long history of human-influenced selection. Comparative genetics in dogs could address the scarcity of non-human neurogenetic systems relevant to human neuropsychiatric disorders, which are characterized by mental, emotional, and behavioral symptoms and involve vastly complex genetic and non-genetic risk factors. Our review describes the diverse behavioral "phenome" of domestic dogs, past and ongoing sources of behavioral selection, and the state of canine behavioral genetics. We highlight two naturally disordered behavioral domains that illustrate how dogs may prove useful as a comparative, forward neurogenetic system: canine age-related cognitive dysfunction, which can be examined more rapidly given the attenuated lifespan of dogs, and compulsive disorders, which may have genetic roots in purpose-bred behaviors. Growing community science initiatives aimed at the companion dog population will be well suited to investigating such complex behavioral phenotypes and offer a comparative resource that parallels human genomic initiatives in scale and dimensionality.

Akkermansia muciniphila, which is enriched in the gut microbiota by metformin, improves cognitive function in aged mice by reducing the proinflammatory cytokine interleukin-6

BackgroundMetformin, a type 2 diabetes treatment, improves the cognitive function of aged mice; however, whether the protective effects of metformin on cognitive function in aged mice are associated with the gut microbiome is poorly understood. Although some studies suggest that the gut microbe composition influences cognitive function and that manipulating the gut microbiota might protect against age-related cognitive dysfunction, there is no direct evidence to validate that the gut microbiota mediates the effect of metformin on cognitive improvement.ResultsIn this study, we show that the gut microbiota is altered by metformin, which is necessary for protection against ageing-associated cognitive function declines in aged mice. Mice treated with antibiotics did not exhibit metformin-mediated cognitive function protection. Moreover, treatment with Akkermansia muciniphila, which is enriched by metformin, improved cognitive function in aged mice. Mechanistically, A. muciniphila decreased pro-inflammatory-associated pathways, particularly that of the pro-inflammatory cytokine interleukin (IL)-6, in both the peripheral blood and hippocampal profiles, which was correlated with cognitive function improvement. An IL-6 antibody protected cognitive function, and an IL-6 recombinant protein abolished the protective effect of A. muciniphila on cognitive function in aged mice. ConclusionThis study reveals that A. muciniphila, which is mediated in the gut microbiota by metformin, modulates inflammation-related pathways in the host and improves cognitive function in aged mice by reducing the pro-inflammatory cytokine IL-6.D24d6SVgEDjFieya1hSRMmVideo Graphical

Ultrasound Imaging Markers of Carotid Atherosclerosis are Associated with Cognition Through Cerebral Small Vessel Disease on MRI (S15.001)

Ultrasound Imaging Markers of Carotid Atherosclerosis are Associated with Cognition Through Cerebral Small Vessel Disease on MRI (S15.001)

Selective inhibition of somatostatin-positive dentate hilar interneurons induces age-related cellular changes and cognitive dysfunction.

The cellular basis of age-related impairments of hippocampal function is not fully understood. In order to evaluate the role of somatostatin-positive (Sst+) interneurons in the dentate gyrus (DG) hilus in this process, we chemogenetically inhibited Sst+ interneurons in the DG hilus. Chronic chemogenetic inhibition (CCI) of these neurons resulted in increased c-Fos staining in the DG hilus, a decrease in the percentage of GAD67- and of Sst-expressing interneurons in the DG, and increased microglial activation in DG, CA3, and CA1. Total dendritic length and spine density were reduced in DG and CA1, suggesting reduced dendritic complexity. Behaviorally, the recognition index in an object recognition task and the percentage of spontaneous alternations in the Y-maze were decreased, while in both initial and reversal learning in the Morris water maze, the latencies to find the hidden platform were increased, suggesting cognitive dysfunction. Our findings establish a causal role for a reduced function of Sst+ interneurons in the DG hilus for cognitive decline and suggest that this reduced function may contribute to age-related impairments of learning and memory. Furthermore, our CCI mice may represent a cellularly defined model of hippocampal aging.

The reverse transcriptase inhibitor 3TC protects against age-related cognitive dysfunction.

Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age-related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease. However, the effects of 3TC on cognitive function with aging have not been investigated. Here, in support of a role for TE transcripts in brain aging/cognitive decline, we show that 3TC: (a) improves cognitive function and reduces neuroinflammation in old wild-type mice; (b) preserves neuronal health with aging in mice and Caenorhabditis elegans; and (c) enhances cognitive function in a mouse model of tauopathy. We also provide insight on potential underlying mechanisms, as well as evidence of translational relevance for these observations by showing that TE transcripts accumulate with brain aging in humans, and that these age-related increases intersect with those observed in Alzheimer's disease. Collectively, our results suggest that TE transcript accumulation during aging may contribute to cognitive decline and neurodegeneration, and that targeting these events with reverse transcriptase inhibitors like 3TC could be a viable therapeutic strategy.

Low-Affinity/High-Selectivity Dopamine Transport Inhibition Sufficient to Rescue Cognitive Functions in the Aging Rat

The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory. Following binding studies to DAT, NET and SERT, GPCR and kinome screening, pharmacokinetics and a basic neurotoxic screen, S-CE-123 was tested for its potential to enhance and/or rescue cognitive functions in young and in aged rats in the non-invasive reward-motivated paradigm of a hole-board test for spatial learning. In addition, an open field study with young rats was carried out. We demonstrated that S-CE-123 is a low-affinity but highly selective dopamine reuptake inhibitor with good bioavailability. S-CE-123 did not induce hyperlocomotion or anxiogenic or stereotypic behaviour in young rats. Our compound improved the performance of aged but not young rats in a reward-motivated task. The well-described impairment of the dopaminergic system in aging may underlie the age-specific effect. We propose S-CE-123 as a possible candidate for developing a tentative therapeutic strategy for age-related cognitive decline and cognitive dysfunction in psychiatric disorders.

Differential associations of mentally-active and passive sedentary behaviours and physical activity with putative cognitive decline in healthy individuals and those with bipolar disorder: Findings from the UK Biobank cohort

ObjectivePhysical activity confers protection against age-related cognitive dysfunction, but less is known about whether cognition is impacted by sedentary behaviour, specifically its mentally-active and passive forms. Both physical inactivity and sedentary behaviour are highly prevalent in bipolar disorder (BD), yet if and how they relate to the disorder's cognitive symptoms remains unclear. In this study, we explored whether individual variation in physical activity and sedentary behaviour was directly associated with cognition and/or moderated the extent of decrements in cognitive performance occurring as a function of age in people with BD versus psychiatrically-healthy controls. MethodsRelevant UK Biobank data were available for 1074 BD patients and 59,653 psychiatrically-healthy controls, aged 40–70. Age, mentally-active (computer use) and passive sedentary behaviour (TV viewing), physical activity, diagnosis, and their interactions were regressed on a global cognitive score. ResultsCognition was inversely associated with physical activity (β = −0.003, CI: −0.003, −0.003) and mentally-passive sedentary behaviour (β = −0.03, CI: −0.04, −0.02) and positively associated with mentally-active sedentary behaviour (β = 0.13, CI: 0.12, 0.15). The latter association was stronger in the BD group. Mentally-active sedentary behaviour moderated the age-cognition association in both BD patients and controls (β = 0.01, CI: 0.008, 0.01), such that age-related decrements in cognition were more apparent in those who engaged in less mentally-active sedentary behaviours compared to those who engaged in more. ConclusionsMentally-active sedentary behaviour may not only attenuate age-related cognitive dysfunction, but may be important for cognition irrespective of age, particularly in those with BD. These findings support the notion that intellectual stimulation is a protective factor conferring cognitive benefits, even in the context of a sedentary lifestyle.

Environmental Enrichment in Murine Models and Its Translation to Human Factors Improving Conditions in Alzheimer Disease

With the aging of the world population, there has been a notable increase in the incidence of Alzheimer disease (AD), the most prevalent neurodegenerative disease affecting the elderly. Several studies have reported a delay in the onset of AD symptoms and age-related cognitive dysfunction upon changes to a healthier lifestyle. These positive adjustments find support in the cognitive reserve hypothesis, which holds that the ability to defer disease inception and protect cognitive performance is related to healthier lifestyle habits such as cognitive and physical activity, social engagement, and sensorial stimulation. These lifestyle habits can be compounded under the umbrella of the environmental enrichment (EE) paradigm. The mechanisms underlying EE's capacity to modulate disease expression remain unclear. Since ethical and methodological considerations rule out direct analysis of such changes in the human brain, researchers have resorted to animal models to carry out in-depth characterizations of post-EE structural and functional brain modifications using a variety of behavioral, electrophysiological, genetic, biochemical, and biophysical approaches. Moreover, given the shorter lifespan of animals compared to humans, it is possible to address the effects of aging in control and AD models. In this review we analyze and classify EE data from studies using AD murine models and compare the setup variables employed. We also delve into various aspects of neuroplasticity, under the posit that this property is the key mechanistic process underlying the benefits of EE in both animal and human subjects.

Protective Effects of Fish (Alaska Pollock) Protein Intake against Short-Term Memory Decline in Senescence-Accelerated Mice.

Dietary fish intake has proven to have health benefits in humans. n-3 polyunsaturated fatty acids (PUFAs) in fish oil (FO), especially, may provide protection against age-related cognitive disorders. Owing to the unique benefits of n-3 PUFAs, other nutrients, such as fish protein (FP), have not been well studied. To clarify the effects of FO and FP on brain function, we investigated whether FO or FP feeding can prevent age-related cognitive dysfunction in senescence-accelerated mouse-prone 10 (SAMP10) mice. The FP group maintained a better working memory compared to the control and FO groups in the Y-maze test, but not episodic memory in the novel object recognition test. To evaluate demyelination levels, we measured neurofilament H (NfH) and myelin basic protein (MBP) immunoreactivity in the hippocampus (Hipp). Axon morphology was maintained in the FP group, but not in the control and FO groups. Additionally, the percentage of positive area for double-staining with NfH/MPB was significantly higher in the Hipp of FP-fed mice than in the control (p &lt; 0.05). These results suggest that FP intake prevents age-related cognitive dysfunction by maintaining axonal morphology in the Hipp of SAMP10 mice.

Mixture of Tomato and Lemon Extracts Synergistically Prevents PC12 Cell Death from Oxidative Stress and Improves Hippocampal Neurogenesis in Aged Mice.

Dietary habits have a great impact on one's health, especially in cognitive decline. Tomato and lemon contain diverse bioactive compounds and possess various effects, including the enhancement of cognitive function. We observed the protective effect of tomato, lemon extract and the mixture of them on H2O2-induced cytotoxicity of PC12 cells. To measure the in vivo effect in a murine model, each extract was orally administered to forty 1-year-old mice for 6 weeks, and a novel object recognition (NOR) test was performed to observe cognitive function, and hippocampal neurogenesis was observed through a doublecortin (DCX) stain. PC12 cell death by oxidative stress was reduced by pretreating with each extract, and a synergistic reduction was observed in the mixture. Newly generated DCX-positive neurons were synergistically increased in the hippocampus by the mixture. NOR test showed a tendency to significantly improve age-related cognitive dysfunction by consuming the mixture of tomato and lemon. In conclusion, tomato and lemon extracts can reduce cellular oxidative stress and increase NOR, likely due to enhanced neurogenesis, while the mixture of the two showed synergistic anti-oxidative effects and hippocampal neurogenesis.

The Role of a Gut Microbial-Derived Metabolite, Trimethylamine N-Oxide (TMAO), in Neurological Disorders.

Trimethylamine lyases are expressed in a wide range of intestinal microbiota which metabolize dietary nutrients like choline, betaine, and L-carnitine to form trimethylamine (TMA). Trimethylamine N-oxide (TMAO) is an oxidative product of trimethylamine (TMA) catalyzed by the action of flavin monooxygenases (FMO) in the liver. Higher levels of TMAO in the plasma and cerebrospinal fluid (CSF) have been shown to contribute to the development of risk factors and actively promote the pathogenesis of metabolic, cardiovascular, and cerebrovascular diseases. The investigations on the harmful effects of TMAO in the development and progression of neurodegenerative and sleep disorders are summarized in this manuscript. Clinical investigations on the role of TMAO in predicting risk factors and prognostic factors in patients with neurological disorders are also summarized. It is observed that the mechanisms underlying TMAO-mediated pathogenesis include activation of inflammatory signaling pathways such as nuclear factor kappa B (NF-κβ), NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, and MAPK/JNK in the periphery and brain. Data suggests that TMAO levels increase with age-related cognitive dysfunction and also induce mitochondrial dysfunction, oxidative stress, neuronal senescence, and synaptic damage in the brain. Further research into the relationships between dietary food consumption and gut microbiota-dependent TMAO levels could provide novel therapeutic options for neurological illnesses.

Unilateral Perforant Path Transection Does Not Alter Lateral Entorhinal Cortical or Hippocampal CA3 Arc Expression.

It is well established that degradation of perforant path fibers is associated with age-related cognitive dysfunction and CA3 hyperactivity. Whether this fiber loss triggers a cascade of other functional changes within the hippocampus circuit has not been causatively established, however. Thus, the current study evaluated the effect of perforant path fiber loss on neuronal activity in CA3 and layer II of the lateral entorhinal cortex (LEC) in relation to mnemonic similarity task performance. Expression of the immediate early gene Arc was quantified in rats that received a unilateral right hemisphere transection of the perforant path or sham surgery that cut the cortex but left the fibers intact. Behavior-related expression of Arc mRNA was measured to test the hypothesis that fiber loss leads to elevated activation of CA3 and LEC neurons, as previously observed in aged rats that were impaired on the mnemonic similarity task. Transection of perforant path fibers, which has previously been shown to lead to a decline in mnemonic similarity task performance, did not alter Arc expression. Arc expression in CA3, however, was correlated with task performance on the more difficult discrimination trials across both surgical groups. These observations further support a link between CA3 activity and mnemonic similarity task performance but suggest the reduced input from the entorhinal cortex to the hippocampus, as observed in old age, does not causatively elevate CA3 activity.

Selective Ablation of Sod2 in Astrocytes Induces Sex-Specific Effects on Cognitive Function, d-Serine Availability, and Astrogliosis.

Cognitive decline is a debilitating aspect of aging and neurodegenerative diseases such as Alzheimer's disease are closely associated with mitochondrial dysfunction, increased reactive oxygen species, neuroinflammation, and astrogliosis. This study investigated the effects of decreased mitochondrial antioxidant response specifically in astrocytes on cognitive performance and neuronal function in C57BL/6J mice using a tamoxifen-inducible astrocyte-specific knockout of manganese superoxide dismutase (aSOD2-KO), a mitochondrial matrix antioxidant that detoxifies superoxide generated during mitochondrial respiration. We reduced astrocyte SOD2 levels in male and female mice at 11-12 months of age and tested in an automated home cage (PhenoTyper) apparatus for diurnal patterns, spatial learning, and memory function at 15 months of age. aSOD2-KO impaired hippocampal-dependent spatial working memory and decreased cognitive flexibility in the reversal phase of the testing paradigm in males. Female aSOD2-KO showed no learning and memory deficits compared with age-matched controls despite significant reduction in hippocampal SOD2 expression. aSOD2-KO males further showed decreased hippocampal long-term potentiation, but paired-pulse facilitation was unaffected. Levels of d-serine, an NMDA receptor coagonist, were also reduced in aSOD2-KO mice, but female knockouts showed a compensatory increase in serine racemase expression. Furthermore, aSOD2-KO mice demonstrated increased density of astrocytes, indicative of astrogliosis, in the hippocampus compared with age-matched controls. These data demonstrate that reduction in mitochondrial antioxidant stress response in astrocytes recapitulates age-related deficits in cognitive function, d-serine availability, and astrogliosis. Therefore, improving astrocyte mitochondrial homeostasis may provide a therapeutic target for intervention for cognitive impairment in aging.SIGNIFICANCE STATEMENT Diminished antioxidant response is associated with increased astrogliosis in aging and in Alzheimer's disease. Manganese superoxide dismutase (SOD2) is an antioxidant in the mitochondrial matrix that detoxifies superoxide and maintains mitochondrial homeostasis. We show that astrocytic ablation of SOD2 impairs hippocampal-dependent plasticity in spatial working memory, reduces long-term potentiation of hippocampal neurons and levels of the neuromodulator d-serine, and increases astrogliosis, consistent with defects in advanced aging and Alzheimer's disease. Our data provide strong evidence for sex-specific effects of astrocytic SOD2 functions in age-related cognitive dysfunction.