Accelerated Aging Characterizes the Early Stage of Alzheimer's Disease.

For Alzheimer's disease (AD), aging is the main risk factor, but whether cognitive impairments due to aging resemble early AD deficits is not yet defined. When working with mouse models of AD, the situation is just as complicated, because only a few studies track the progression of the disease at different ages, and most ignore how the aging process affects control mice. In this work, we addressed this problem by comparing the aging process of PS2APP (AD) and wild-type (WT) mice at the level of spontaneous brain electrical activity under anesthesia. Using local field potential recordings, obtained with a linear probe that traverses the posterior parietal cortex and the entire hippocampus, we analyzed how multiple electrical parameters are modified by aging in AD and WT mice. With this approach, we highlighted AD specific features that appear in young AD mice prior to plaque deposition or that are delayed at 12 and 16 months of age. Furthermore, we identified aging characteristics present in WT mice but also occurring prematurely in young AD mice. In short, we found that reduction in the relative power of slow oscillations (SO) and Low/High power imbalance are linked to an AD phenotype at its onset. The loss of SO connectivity and cortico-hippocampal coupling between SO and higher frequencies as well as the increase in UP-state and burst durations are found in young AD and old WT mice. We show evidence that the aging process is accelerated by the mutant PS2 itself and discuss such changes in relation to amyloidosis and gliosis.

Long-term dynamics of aberrant neuronal activity in awake Alzheimer's disease transgenic mice.

Alzheimer's disease (AD) is associated with aberrant neuronal activity, which is believed to critically determine disease symptoms. How these activity alterations emerge, how stable they are over time, and whether cellular activity dynamics are affected by the amyloid plaque pathology remains incompletely understood. We here repeatedly recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice over four weeks during the early phase of plaque deposition using in vivo two-photon calcium imaging. We found that aberrant activity during this stage largely persisted over the observation time. Novel highly active neurons slowly emerged from former intermediately active neurons. Furthermore, activity fluctuations were independent of plaque proximity, but aberrant activity was more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in models of cerebral amyloidosis is the consequence of persistent single cell aberrant neuronal activity, a finding of potential diagnostic and therapeutic relevance for AD.

Inhalational Anesthetics Do Not Deteriorate Amyloid-ß-Derived Pathophysiology in Alzheimer's Disease: Investigations on the Molecular, Neuronal, and Behavioral Level.

BACKGROUND: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-ß (Aß) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. OBJECTIVE: In the present study, we want to detail the interactions of inhalational anesthetics with Aß-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aß oligomerization and Aß-mediated neurotoxicity on processes related to cognition. METHODS: Oligomerization of Aß1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aß1-42, Aß1-40, pyroglutamate-modified amyloid-(AßpE3), and nitrated Aß (3NTyrAß), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aß plaque burden in transgenic AD mice (ArcAß) after anesthesia. RESULTS: Whereas isoflurane and sevoflurane did not affect Aß1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AßpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aß1-42-induced spine density attenuation. In the presence of Aß1-40 and AßpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aß1-42 or 3NTyrAß, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAß mice. CONCLUSION: None of the anesthetics aggravated Aß-derived AD pathology in vivo. However, Aß and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aß1-42 aggregation, LTP, and spine density.

Common Factors of Alzheimer's Disease and Rheumatoid Arthritis-Pathomechanism and Treatment.

The accumulation of amyloid plaques, or misfolded fragments of proteins, leads to the development of a condition known as amyloidosis, which is clinically recognized as a systemic disease. Amyloidosis plays a special role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and rheumatoid arthritis (RA). The occurrence of amyloidosis correlates with the aging process of the organism, and since nowadays, old age is determined by the comfort of functioning and the elimination of unpleasant disease symptoms in the elderly, exposure to this subject is justified. In Alzheimer's disease, amyloid plaques negatively affect glutaminergic and cholinergic transmission and loss of sympathetic protein, while in RA, amyloids stimulated by the activity of the immune system affect the degradation of the osteoarticular bond. The following monograph draws attention to the over-reactivity of the immune system in AD and RA, describes the functionality of the blood-brain barrier as an intermediary medium between RA and AD, and indicates the direction of research to date, focusing on determining the relationship and the cause-effect link between these disorders. The paper presents possible directions for the treatment of amyloidosis, with particular emphasis on innovative therapies.

Controversial Approval of New Drug to Treat Alzheimer's Disease.

Aducanumab (Aduhelm), the first new drug to treat Alzheimer's disease since 2003, has received accelerated approval from the Food and Drug Administration (FDA).This drug's approval has been highly contentious in the medical and scientific community owing to contradictory study findings and the FDA's advisory panel not recommending its approval.

Longitudinal assessment of amyloid-beta deposition in initially amyloid-negative non-demented individuals with [11C]-PIB PET imaging.

ABSTRACT: This study aimed to assess the longitudinal changes in amyloid beta (Aß) deposition in cortical regions with [11C]-PIB PET in initially amyloid-negative non-demented subjects and evaluate whether amyloid-negative subjects convert to amyloid-positive.Sixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (aged 60-75 years), who were amyloid-negative at baseline, underwent 60-minute dynamic [11C]-PIB PET and cognitive assessment over 5.0 to 9.4 years of a long follow-up, and the apolipoprotein-E (APOE) genotype was assessed. Regions of interest were defined in the bilateral cortex on coregistered MRI. Quantitative analysis of [11C]-PIB was performed using the distribution value ratio (DVR). Longitudinal changes in global and regional PIB DVRs were evaluated in the same regions, and the annual rate of change in the PIB DVR was calculated.Seven (30.4%) of 23 initially amyloid-negative non-demented subjects converted to globally amyloid-positive (global PIB DVR ≥1.40) over a follow-up of 6.5 ±â€Š1.4 years (converter). The global PIB DVR in converters increased from 1.22 ±â€Š0.07 at baseline to 1.63 ±â€Š0.15 (n = 7, P < .01) at last follow-up, and an annual increase of global PIB DVR was 0.057 ±â€Š0.019/year (n = 7, P < .01). In contrast, the global PIB DVR in the remaining 16 subjects was 1.15 ±â€Š0.07 at baseline and did not change over a follow-up period (stable). The APOE ε4 allele was present in 4 (57.1%) of the 7 converters, differing from 2 (12.5%) of 16 stable subjects (Fisher's exact test, P < .05). Three amyloid-negative MCI subjects had an annual increase in global PIB DVR above 0.061/year and became positive at 2.8 ±â€Š0.5 years of follow-up, which was faster than 5.0 ±â€Š2.0 years in 4 CN subjects. The regional PIB DVR that increased early above the regional positivity threshold was most frequently found in the right lateral temporal cortex (71.4%), followed by the left frontal cortex (41.8%).Our results suggest that the initially amyloid-negative CN and MCI subjects, especially with APOE ε4, can become globally amyloid-positive over a longer time, based on early regional Aß deposition in the lateral temporal cortex and/or frontal cortex.

Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3-4 months old) infused with oligomeric Aß peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aß plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders.

A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses.

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimer's disease. PGRN is highly expressed in the microglia near Aß plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and Aß levels in the young male but not female mice. PGRN-deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, galectin-3, TREM2, and GPNMB, specifically near Aß plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN-deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to Aß fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on APP metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia.

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aß Plaques.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-ß (Aß) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aß plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aß plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aß plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aß plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.

The AppNL-G-F mouse retina is a site for preclinical Alzheimer's disease diagnosis and research.

In this study, we report the results of a comprehensive phenotyping of the retina of the AppNL-G-F mouse. We demonstrate that soluble Aß accumulation is present in the retina of these mice early in life and progresses to Aß plaque formation by midlife. This rising Aß burden coincides with local microglia reactivity, astrogliosis, and abnormalities in retinal vein morphology. Electrophysiological recordings revealed signs of neuronal dysfunction yet no overt neurodegeneration was observed and visual performance outcomes were unaffected in the AppNL-G-F mouse. Furthermore, we show that hyperspectral imaging can be used to quantify retinal Aß, underscoring its potential as a biomarker for AD diagnosis and monitoring. These findings suggest that the AppNL-G-F retina mimics the early, preclinical stages of AD, and, together with retinal imaging techniques, offers unique opportunities for drug discovery and fundamental research into preclinical AD.

Atrial fibrillation and Alzheimer's disease: A conundrum.

During ageing, the prevalence of Alzheimer's disease (AD) and of cardiovascular disease CVD) increases. Our aim is to investigate the relationship between AD and CVD and its risk factors, with a view to explaining the underlying mechanisms of this association. This review is based on the material obtained via MEDLINE (PubMed), Embase and Clinical Trials databases, from January 1980 until May 2019. The search term used was "Alzheimer's disease", combined with "cardiovascular disease", "hypertension", "dyslipidaemia", "diabetes mellitus", "atrial fibrillation", "coronary artery disease", "heart valve disease", "heart failure". Out of the 1328 papers initially retrieved, 431 duplicates and 216 records in languages other than English were removed; thus, only 98 papers were included in our research material. We have found that AD and CVD are frequently associated, while both of them, alone may be considered deleterious to health, the study of their combination constitutes a clinical challenge. Further research will help to clarify the real impact of CVD and its risk factors on AD, in order to better comprehend the effects of subclinical and clinical cardiovascular diseases on the brain. It may be hypothesized that there are various mechanisms underlying the association between AD and CVD, the main ones being: hypoperfusion and emboli, atherosclerosis, furthermore in both the heart and brain of AD patients, amyloid deposits may be present, thus causing damage to these organs. We need to clarify the real impact of these underlying hypothesized mechanisms and to investigate gender issues.

Aß-Induced Damage Memory in hCMEC/D3 Cells Mediated by Sirtuin-1.

It is well accepted by the scientific community that the accumulation of beta-amyloid (Aß) may be involved in endothelial dysfunction during Alzheimer's disease (AD) progression; however, anti-Aß anti-bodies, which remove Aß plaques, do not improve cerebrovascular function in AD animal models. The reasons for these paradoxical results require investigation. We hypothesized that Aß exposure may cause persistent damage to cerebral endothelial cells even after Aß is removed (referred to as cerebrovascular endothelial damage memory). In this study, we aimed to investigate whether cerebrovascular endothelial damage memory exists in endothelial cells. hCMEC/D3 cells were treated with Aß1-42 for 12 h and then Aß1-42 was withdrawn for another 12 h incubation to investigate whether cerebrovascular endothelial damage memory exists in endothelial cells. A mechanism-based kinetics progression model was developed to investigate the dynamic characters of the cerebrovascular endothelial damage. After Aß1-42 was removed, the sirt-1 levels returned to normal but the cell vitality did not improve, which suggests that cerebrovascular endothelial damage memory may exist in endothelial cells. Sirt-1 activator SRT2104 and NAD+ (Nicotinamide Adenine Dinucleotide) supplement may dose-dependently relieve the cerebrovascular endothelial damage memory. sirt-1 inhibitor EX527 may exacerbate the cerebrovascular endothelial damage memory. Kinetics analysis suggested that sirt-1 is involved in initiating the cerebrovascular endothelial damage memory; otherwise, NAD+ exhaustion plays a vital role in maintaining the cerebrovascular endothelial damage memory. This study provides a novel feature of cerebrovascular endothelial damage induced by Aß.

Electrophysiological and Imaging Calcium Biomarkers of Aging in Male and Female 5×FAD Mice.

BACKGROUND: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer's disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-ß production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker. OBJECTIVE: Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD mice on a C57BL/6 genetic background using sharp electrodes coupled with Oregon-green Bapta-1 imaging. We focused on three ages that coincide with the course of amyloid deposition: 1.5, 4, and 10 months old. METHODS: Outcome variables included measures of the afterhyperpolarization, short-term synaptic plasticity, and calcium kinetics during synaptic activation. Quantitative analyses of spatial learning and memory were also conducted using the Morris water maze. Main effects of sex, age, and genotype were identified on measures of electrophysiology and calcium imaging. RESULTS: Measures of resting Oregon-green Bapta-1 fluorescence showed significant reductions in the 5×FAD group compared to controls. Deficits in spatial memory, along with increases in Aß load, were detectable at older ages, allowing us to test for temporal associations with the onset of calcium dysregulation. CONCLUSION: Our results provide evidence that reduced, rather than elevated, neuronal calcium is identified in this 5×FAD model and suggests that this surprising result may be a novel biomarker of AD.

Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs.

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABAB antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.

Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer's Disease.

Alzheimer's disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aß) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aß peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aß peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer's pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.

Caspase-6 Knockout in the 5xFAD Model of Alzheimer's Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-ß plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.

Aß oligomers trigger and accelerate Aß seeding.

Aggregation of amyloid-ß (Aß) that leads to the formation of plaques in Alzheimer's disease (AD) occurs through the stepwise formation of oligomers and fibrils. An earlier onset of aggregation is obtained upon intracerebral injection of Aß-containing brain homogenate into human APP transgenic mice that follows a prion-like seeding mechanism. Immunoprecipitation of these brain extracts with anti-Aß oligomer antibodies or passive immunization of the recipient animals abrogated the observed seeding activity, although induced Aß deposition was still evident. Here, we establish that, together with Aß monomers, Aß oligomers trigger the initial phase of Aß seeding and that the depletion of oligomeric Aß delays the aggregation process, leading to a transient reduction of seed-induced Aß deposits. This work extends the current knowledge about the role of Aß oligomers beyond its cytotoxic nature by pointing to a role in the initiation of Aß aggregation in vivo. We conclude that Aß oligomers are important for the early initiation phase of the seeding process.

Optogenetic gamma stimulation rescues memory impairments in an Alzheimer's disease mouse model.

Slow gamma oscillations (30-60 Hz) correlate with retrieval of spatial memory. Altered slow gamma oscillations have been observed in Alzheimer's disease. Here, we use the J20-APP AD mouse model that displays spatial memory loss as well as reduced slow gamma amplitude and phase-amplitude coupling to theta oscillations phase. To restore gamma oscillations in the hippocampus, we used optogenetics to activate medial septal parvalbumin neurons at different frequencies. We show that optogenetic stimulation of parvalbumin neurons at 40 Hz (but not 80 Hz) restores hippocampal slow gamma oscillations amplitude, and phase-amplitude coupling of the J20 AD mouse model. Restoration of slow gamma oscillations during retrieval rescued spatial memory in mice despite significant plaque deposition. These results support the role of slow gamma oscillations in memory and suggest that optogenetic stimulation of medial septal parvalbumin neurons at 40 Hz could provide a novel strategy for treating memory deficits in AD.

Microglia in Brain Development, Homeostasis, and Neurodegeneration.

Advances in human genetics have implicated a growing number of genes in neurodegenerative diseases, providing insight into pathological processes. For Alzheimer disease in particular, genome-wide association studies and gene expression studies have emphasized the pathogenic contributions from microglial cells and motivated studies of microglial function/dysfunction. Here, we summarize recent genetic evidence for microglial involvement in neurodegenerative disease with a focus on Alzheimer disease, for which the evidence is most compelling. To provide context for these genetic discoveries, we discuss how microglia influence brain development and homeostasis, how microglial characteristics change in disease, and which microglial activities likely influence the course of neurodegeneration. In all, we aim to synthesize varied aspects of microglial biology and highlight microglia as possible targets for therapeutic interventions in neurodegenerative disease.