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Nuclear pore complexes (NPCs) are highly dynamic macromolecular protein structures that facilitate molecular exchange across the nuclear envelope. Aberrant NPC functioning has been implicated in neurodegeneration. The translocated promoter region (Tpr) is a critical scaffolding nucleoporin (Nup) of the nuclear basket, facing the interior of the NPC. However, the role of Tpr in adult neural stem/precursor cells (NSPCs) in Alzheimer's disease (AD) is unknown. Using super-resolution (SR) and electron microscopy, we defined the different subcellular localizations of Tpr and phospho-Tpr (P-Tpr) in NSPCs in vitro and in vivo. Elevated Tpr expression and reduced P-Tpr nuclear localization accompany NSPC differentiation along the neurogenic lineage. In 5xFAD mice, an animal model of AD, increased Tpr expression in DCX+ hippocampal neuroblasts precedes increased neurogenesis at an early stage, before the onset of amyloid-β plaque formation. Whereas nuclear basket Tpr interacts with chromatin modifiers and NSPC-related transcription factors, P-Tpr interacts and co-localizes with cyclin-dependent kinase 1 (Cdk1) at the nuclear chromatin of NSPCs. In hippocampal NSPCs in a mouse model of AD, aberrant Tpr expression was correlated with altered NPC morphology and counts, and Tpr was aberrantly expressed in postmortem human brain samples from patients with AD. Thus, we propose that altered levels and subcellular localization of Tpr in CNS disease affect Tpr functionality, which in turn regulates the architecture and number of NSPC NPCs, possibly leading to aberrant neurogenesis.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) which ultimately forms plaques. These Aβ deposits can be induced in APP transgenic mouse models by prion-like seeding. It has been widely accepted that anosmia and hyposmia occur during the early stages of AD, even before cognitive deficits are present. In order to determine the impact of seed-induced Aβ deposits on olfaction, we performed intracerebral injections of seed-competent brain homogenate into the olfactory bulb of young pre-depositing APP transgenic mice. Remarkably, we observed a dramatic olfactory impairment in those mice. Furthermore, the number of newborn neurons as well as the activity of cells in the mitral cell layer was decreased. Notably, exposure to an enriched environment reduced Aβ seeding, vivified neurogenesis and most importantly reversed olfactory deficits. Based on our findings, we conclude that altered neuronal function as a result of induced Aβ pathology might contribute to olfactory dysfunction in AD., (© 2022. The Author(s).)

Neuropathologically, Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta peptide (Aβ) and subsequent formation of the so-called Aβ plaques. Along with neuronal loss, previous studies report white matter anomalies and corpus callosum (CC) atrophy in AD patients. Notably, perturbations in the white matter can be observed years before expected disease onset, suggesting that early stages of disease progression play a role in AD-associated loss of myelin integrity. Through seed-induced deposition of Aβ, we are able to examine alterations of central nervous system (CNS) integrity during the initial stages of plaque formation. In this study, we investigate the impact of Aβ seeding in the CC utilizing various imaging techniques as well as quantitative gene expression analysis and demonstrate that Aβ deposits result in an imbalance of glial cells in the CC. We found increased amounts of phagocytic microglia and reactive astrocytes, while oligodendrocyte progenitor cell (OPC) numbers were reduced. Moreover, white matter aberrations adjacent to the Aβ seeding were observed together with an overall decline in callosal myelination. This data indicate that the initial stages of plaque formation induce oligodendrocyte dysfunction, which might ultimately lead to myelin loss., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aires, Ziegler-Waldkirch, Friesen, Reichardt, Erny, Loreth, Harborne, Kretz, von Elverfeldt and Meyer-Luehmann.)

Several degenerative brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the simultaneous appearance of amyloid-β (Aβ) and α-synuclein (α-syn) pathologies and symptoms that are similar, making it difficult to differentiate between these diseases. Until now, an accurate diagnosis can only be made by postmortem analysis. Furthermore, the role of α-syn in Aβ aggregation and the arising characteristic olfactory impairments observed during the progression of these diseases is still not well understood. Therefore, we assessed Aβ load in olfactory bulbs of APP-transgenic mice expressing APP695 KM670/671NL and PSEN1 L166P under the control of the neuron-specific Thy-1 promoter (referred to here as APPPS1) and APPPS1 mice co-expressing SNCA A30P (referred to here as APPPS1 × [A30P]aSYN). Furthermore, the olfactory capacity of these mice was evaluated in the buried food and olfactory avoidance test. Our results demonstrate an age-dependent increase in Aβ load in the olfactory bulb of APP-transgenic mice that go along with exacerbated olfactory performance. Our study provides clear evidence that the presence of α-syn significantly diminished the endogenous and seed-induced Aβ deposits and significantly ameliorated olfactory dysfunction in APPPS1 × [A30P]aSYN mice., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Microglia appear activated in the vicinity of amyloid beta (Aβ) plaques, but whether microglia contribute to Aβ propagation into unaffected brain regions remains unknown. Using transplantation of wild-type (WT) neurons, we show that Aβ enters WT grafts, and that this is accompanied by microglia infiltration. Manipulation of microglia function reduced Aβ deposition within grafts. Furthermore, in vivo imaging identified microglia as carriers of Aβ pathology in previously unaffected tissue. Our data thus argue for a hitherto unexplored mechanism of Aβ propagation., (© 2021. The Author(s).)

Aggregation of amyloid-β (Aβ) 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 Aβ-containing brain homogenate into human APP transgenic mice that follows a prion-like seeding mechanism. Immunoprecipitation of these brain extracts with anti-Aβ oligomer antibodies or passive immunization of the recipient animals abrogated the observed seeding activity, although induced Aβ deposition was still evident. Here, we establish that, together with Aβ monomers, Aβ oligomers trigger the initial phase of Aβ seeding and that the depletion of oligomeric Aβ delays the aggregation process, leading to a transient reduction of seed-induced Aβ deposits. This work extends the current knowledge about the role of Aβ oligomers beyond its cytotoxic nature by pointing to a role in the initiation of Aβ aggregation in vivo. We conclude that Aβ oligomers are important for the early initiation phase of the seeding process., (© 2019 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Synapse loss has detrimental effects on cellular communication, leading to network disruptions within the central nervous system (CNS) such as in Alzheimer's disease (AD). AD is characterized by a progressive decline of memory function, cognition, neuronal and synapse loss. The two main neuropathological hallmarks are amyloid-β (Aβ) plaques and neurofibrillary tangles. In the brain of AD patients and in mouse models of AD several morphological and functional changes, such as microgliosis and astrogliosis around Aβ plaques, as well as dendritic and synaptic alterations, are associated with these lesions. In this review article, we will summarize the current literature on synapse loss in mouse models of AD and discuss current and prospective treatments for AD.

Several studies suggest that women have a higher risk to develop Alzheimer's disease (AD) than men. In particular, the number of pregnancies was shown to be a risk factor for AD and women with several pregnancies on average had an earlier onset of the disease, thus making childbearing a risk factor. However, the impact of being pregnant on Aβ plaque pathology and adult neurogenesis still remains elusive. Postmortem analysis revealed that pregnant 5xFAD transgenic mice had significantly more Aβ plaques in the hippocampus from G10 onwards and that the number of Ki67 and DCX positive cells dramatically decreased during the postpartum period. Furthermore, 5 months old 5xFAD transgenic mice that also nursed their offsprings for 4 weeks had a similar Aβ plaque load than merely pregnant mice, indicating that pregnancy alone is sufficient to elevate Aβ plaque levels. Interestingly, housing in an enriched environment reduced the Aβ plaque load and vivified neurogenesis. Our results suggest that pregnancy alters Aβ plaque deposition in 5xFAD transgenic mice and diminishes the generation of newborn neurons. We conclude that pregnancy alone is sufficient to induce this phenotype that can be reversed upon environmental enrichment.

Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival. In contrast, Hdac1 and Hdac2 were not required for adult microglia survival during homeostasis. In a mouse model of Alzheimer's disease, deletion of Hdac1 and Hdac2 in microglia, but not in neuroectodermal cells, resulted in a decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a role for epigenetic factors that differentially affect microglia development, homeostasis, and disease that could potentially be utilized therapeutically., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is characterized by severe neuronal loss as well as the accumulation of amyloid-β (Aβ), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Aβ can be initiated by prion-like seeding, the impact and functional consequences of induced Aβ deposits (Aβ seeding) on neurons still remain open questions. Here, we find that Aβ seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two APP transgenic mouse models. We further demonstrate that neuronal cell death occurs primarily in the vicinity of induced Aβ deposits culminating in electrophysiological abnormalities. Notably, environmental enrichment and voluntary exercise not only revives adult neurogenesis and reverses memory deficits but, most importantly, prevents Aβ seeding by activated, phagocytic microglia cells. Our work expands the current knowledge regarding Aβ seeding and the consequences thereof and attributes microglia an important role in diminishing Aβ seeding by environmental enrichment., (© 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)