Corpora amylacea negatively correlate with hippocampal tau pathology in Alzheimer's disease.

Introduction: Severity and distribution of aggregated tau and neurofibrillary tangles (NFT) are strongly correlated with the clinical presentation of Alzheimer's disease (AD). Clearance of aggregated tau could decrease the rate of NFT formation and delay AD onset. Recent studies implicate corpora amylacea (CA) as a regulator of onset or accumulation of tau pathology. Normally, CA clear brain waste products by amassing cellular debris, which are then extruded into the cerebrospinal fluid to be phagocytosed. The proper functioning of CA may slow progression of AD-associated NFT pathology, and this relationship may be influenced by amount and distribution of phospho-tau (pTau) produced, age, sex, and genetic risk. Objective: The goal of this study was to determine if CA size and number are associated with hippocampal location and local pTau severity while accounting for variations in age, sex, and genetic risk. Methods: Postmortem brain hippocampal tissue sections from 40 AD and 38 unaffected donors were immunohistochemically stained with AT8 (pTau) and counter stained with periodic acid Schiff (PAS). Stained sections of the CA1 and CA3 regions of the hippocampus were analyzed. The percent area occupied (%AO) of CA, pTau, and NFT was calculated. Pairwise comparisons and regression modeling were used to analyze the influence of age, pTau %AO, and genetic risk on %AO by CA in each region, separately in donors with AD and unaffected donors. Results: CA %AO was significantly higher in the CA3 region compared to CA1 in both groups. A significant negative correlation of CA %AO with both pTau %AO and neurofibrillary tangle %AO in the CA3 region of AD brain donors was found. Regression analysis in the CA3 region revealed a significant negative association between CA with both pTau and age. Conclusion: We found an increase of CA in the CA3 region, compared to CA1 region, in AD and unaffected donors. This may suggest that the CA3 region is a hub for waste removal. Additionally, the negative correlation between %AO by CA and NFT in the CA3 region of the hippocampus in donors with AD suggests CA could play a role in AD pathologic progression by influencing tau clearance.

Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer's mouse model.

BACKGROUND: Alzheimer's disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined. METHODS: Circuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression. RESULTS: We identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons. CONCLUSION: We report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission.

Corpora amylacea are associated with tau burden and cognitive status in Alzheimer's disease.

Corpora amylacea (CA) and their murine analogs, periodic acid Schiff (PAS) granules, are age-related, carbohydrate-rich structures that serve as waste repositories for aggregated proteins, damaged cellular organelles, and other cellular debris. The structure, morphology, and suspected functions of CA in the brain imply disease relevance. Despite this, the link between CA and age-related neurodegenerative diseases, particularly Alzheimer's disease (AD), remains poorly defined. We performed a neuropathological analysis of mouse PAS granules and human CA and correlated these findings with AD progression. Increased PAS granule density was observed in symptomatic tau transgenic mice and APOE knock-in mice. Using a cohort of postmortem AD brain samples, we examined CA in cognitively normal and dementia patients across Braak stages with varying APOE status. We identified a Braak-stage dependent bimodal distribution of CA in the dentate gyrus, with CA accumulating and peaking by Braak stages II-III, then steadily declining with increasing tau burden. Refined analysis revealed an association of CA levels with both cognition and APOE status. Finally, tau was detected in whole CA present in human patient cerebrospinal fluid, highlighting CA-tau as a plausible prodromal AD biomarker. Our study connects hallmarks of the aging brain with the emergence of AD pathology and suggests that CA may act as a compensatory factor that becomes depleted with advancing tau burden.

The neurogenic niche in Alzheimer's disease.

Adult hippocampal neurogenesis is the process of generation and functional incorporation of new neurons, formed by adult neural stem cells in the dentate gyrus. Adult hippocampal neurogenesis is highly dependent upon the integration of dynamic external stimuli and is instrumental in the formation of new spatial memories. Adult hippocampal neurogenesis is therefore uniquely sensitive to the summation of neuronal circuit and neuroimmune environments that comprise the neurogenic niche, and has powerful implications in diseases of aging and neurological disorders. This sensitivity underlies the neurogenic niche alterations commonly observed in Alzheimer's disease, the most common form of dementia. This review summarizes Alzheimer's disease associated changes in neuronal network activity, neuroinflammatory processes, and adult neural stem cell fate choice that ultimately result in neurogenic niche dysfunction and impaired adult hippocampal neurogenesis. A more comprehensive understanding of the complex changes mediating neurogenic niche disturbances in Alzheimer's disease will aid development of future therapies targeting adult neurogenesis.

Neuropeptides Modulate Local Astrocytes to Regulate Adult Hippocampal Neural Stem Cells.

Neural stem cells (NSCs) in the dentate gyrus (DG) reside in a specialized local niche that supports their neurogenic proliferation to produce adult-born neurons throughout life. How local niche cells interact at the circuit level to ensure continuous neurogenesis from NSCs remains unknown. Here we report the role of endogenous neuropeptide cholecystokinin (CCK), released from dentate CCK interneurons, in regulating neurogenic niche cells and NSCs. Specifically, stimulating CCK release supports neurogenic proliferation of NSCs through a dominant astrocyte-mediated glutamatergic signaling cascade. In contrast, reducing dentate CCK induces reactive astrocytes, which correlates with decreased neurogenic proliferation of NSCs and upregulation of genes involved in immune processes. Our findings provide novel circuit-based information on how CCK acts on local astrocytes to regulate the key behavior of adult NSCs.

The Accumulation of Tau-Immunoreactive Hippocampal Granules and Corpora Amylacea Implicates Reactive Glia in Tau Pathogenesis during Aging.

The microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.

A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation.

Abnormal intracellular accumulation of aggregated tau is a hallmark feature of Alzheimer's disease and other tauopathies. Pathological tau can undergo a range of post-translational modifications (PTMs) that are implicated as triggers of disease pathology. Recent studies now indicate that tau acetylation, in particular, controls both microtubule binding and tau aggregation, thereby acting as a central regulator of tau's biochemical properties and providing avenues to exploit for potential therapies. Here, using cell-based assays and tau transgenic mice harboring an acetylation-mimic mutation at residue Lys-280 (K280Q), we evaluated whether this substitution modifies the neurodegenerative disease pathology associated with the aggregate-prone tau P301S variant. Strikingly, the addition of a K280Q-substituted variant altered P301S-mediated tau conformation and reduced tau hyperphosphorylation. We further evaluated neurodegeneration markers in K280Q acetylation-mimic mice and observed reduced neuroinflammation as well as restored levels of N-methyl-d-aspartate receptors and post-synaptic markers compared with the parental mice. Thus, substituting a single lysine residue in the context of a P301S disease-linked mutation produces a unique tau species that abrogates some of the cardinal features of tauopathy. The findings of our study indicate that a complex tau PTM code likely regulates tau pathogenesis, highlighting the potential utility of manipulating and detoxifying tau strains through site-specific tau-targeting approaches.

Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program.

TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein.

A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy.

Tau acetylation has recently emerged as a dominant post-translational modification (PTM) in Alzheimer's disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule (MT)-binding region (MTBR), suggesting acetylation could regulate both normal and pathological tau functions. Here, we combined biochemical and cell-based approaches to uncover a dual pathogenic mechanism mediated by tau acetylation. We show that acetylation specifically at residues K280/K281 impairs tau-mediated MT stabilization, and enhances the formation of fibrillar tau aggregates, highlighting both loss and gain of tau function. Full-length acetylation-mimic tau showed increased propensity to undergo seed-dependent aggregation, revealing a potential role for tau acetylation in the propagation of tau pathology. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds. Our study identifies a potential "two-hit" mechanism in which tau acetylation disengages tau from MTs and also promotes tau aggregation. Thus, therapeutic approaches to limit tau K280/K281 acetylation could simultaneously restore MT stability and ameliorate tau pathology in AD and related tauopathies.