Aβ oligomers trigger and accelerate Aβ seeding

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

Tpr Misregulation in Hippocampal Neural Stem Cells in Mouse Models of Alzheimer’s Disease

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

Environmental enrichment reverses Aβ pathology during pregnancy in a mouse model of Alzheimer’s disease

Abstract 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

Histone Deacetylases 1 and 2 Regulate Microglia Function during Development, Homeostasis, and Neurodegeneration in a Context-Dependent Manner

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

Microglia contribute to the propagation of A beta into unaffected brain tissue

Microglia appear activated in the vicinity of amyloid beta (A beta) plaques, but whether microglia contribute to A beta propagation into unaffected brain regions remains unknown. Using transplantation of wild-type (WT) neurons, we show that A beta enters WT grafts, and that this is accompanied by microglia infiltration. Manipulation of microglia function reduced A beta deposition within grafts. Furthermore, in vivo imaging identified microglia as carriers of A beta pathology in previously unaffected tissue. Our data thus argue for a hitherto unexplored mechanism of A beta propagation. This study shows that A beta from transgenic host tissue is able to enter and deposit within wild-type grafts via microglia, thus identifying microglia as carriers of A beta deposition into previously unaffected brain tissue