Neuritic plaques, a pathological hallmark in Alzheimer’s disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aβ) peptide and degenerating neurites that accumulate autolysosomes. We found that, in the brains of patients with AD and in AD mouse models, Aβ plaque-associated Olig2- and NG2-expressing oligodendrocyte progenitor cells (OPCs), but not astrocytes, microglia, or oligodendrocytes, exhibit a senescence-like phenotype characterized by the upregulation of p21/CDKN1A, p16/INK4/CDKN2A proteins, and senescence-associated β-galactosidase activity. Molecular interrogation of the Aβ plaque environment revealed elevated levels of transcripts encoding proteins involved in OPC function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aβ triggered cell senescence. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened Aβ load, and ameliorated cognitive deficits. Our findings suggest a role for Aβ-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments.

In response to endoplasmic reticulum (ER) stress, cells launch homeostatic and protective responses, but can also activate cell death cascades. A 54 kDa integral ER membrane protein called Herp was identified as a stress-responsive protein in non-neuronal cells. We report that Herp is present in neurons in the developing and adult brain, and that it is regulated in neurons by ER stress; sublethal levels of ER stress increase Herp levels, whereas higher doses decrease Herp levels and induce apoptosis. The endoplasmic reticulum (ER) 1 is a unique cellular compartment simultaneously involved in the processes of protein synthesis and Ca 2ϩ homeostasis. Various conditions, including oxidative and metabolic stress and Ca 2ϩ overload can interfere with ER functions leading to the accumulation of misfolded proteins. Cells sense and respond to such ER stress by activating a signaling cascade termed the unfolded protein response, which results in the transcriptional up-regulation of stress proteins including members of the glucose-regulated protein (grp) family and other protein chaperones (calnexin, calreticulin, ERp72) that enhance the protein folding capability of the ER (1). ER stress has been documented in neurons in a variety of acute pathological conditions including cerebral ischemia and severe epileptic seizures (2). However, despite the fact that disruption of cellular Ca 2ϩ homeostasis contributes to the death of neurons in these conditions, it is not known how molecular responses to ER stress modify cellular Ca 2ϩ homeostasis and the cell death process. Studies of cultured cells suggest that ER stress can stimulate the expression of cytoprotective genes such as protein chaperones (3) but may also trigger a form of programmed cell death called apoptosis (4), which may involve activation of ER-associated caspases and transcription factors such as Gadd153. A better understanding of ER stress and its links to cell survival/death decisions is therefore needed.Recent findings suggest that ER stress is also implicated in several chronic neurodegenerative disorders including Alzheimer's (5, 6), Parkinson's (7), and Huntington's (8) diseases. Alzheimer's disease (AD) results from altered proteolytic processing of the amyloid precursor protein (APP), resulting in aggregation of neurotoxic forms of amyloid ␤-peptide (A␤) (9). Exposure of cultured neurons to A␤-peptide, and metabolic and oxidative insults can induce an ER stress response (6, 10). Moreover, mutations in presenilin-1 (PS1) that cause earlyonset familial AD perturb ER Ca 2ϩ homeostasis (11, 12) and impair the ability of neurons to engage a cytoprotective ER stress response (20). The adverse effects of A␤ and PS1 mutations on ER function may sensitize neurons to excitotoxicity and apoptosis (11).A novel 54 kDa protein called Herp (homocysteine-induced ER protein) was recently identified and characterized as a stress-responsive protein localized in the ER membrane; Herp contains a ubiquitin-like domain and resembles the human DNA excision repair protein hHR23 ...

CHD5 is frequently deleted in neuroblastoma and is a tumor suppressor gene. However, little is known about the role of CHD5 other than it is homologous to chromatin remodeling ATPases. We found CHD5 mRNA was restricted to the brain; by contrast, most remodeling ATPases were broadly expressed. CHD5 protein isolated from mouse brain was associated with HDAC2, p66ß, MTA3 and RbAp46 in a megadalton complex. CHD5 protein was detected in several rat brain regions and appeared to be enriched in neurons. CHD5 protein was predominantly nuclear in primary rat neurons and brain sections. Microarray analysis revealed genes that were upregulated and downregulated when CHD5 was depleted from primary neurons. CHD5 depletion altered expression of neuronal genes, transcription factors, and brain-specific subunits of the SWI/SNF remodeling enzyme. Expression of gene sets linked to aging and Alzheimer's disease were strongly altered by CHD5 depletion from primary neurons. Chromatin immunoprecipitation revealed CHD5 bound to these genes, suggesting the regulation was direct. Together, these results indicate that CHD5 protein is found in a NuRD-like multi-protein complex. CHD5 expression is restricted to the brain, unlike the closely related family members CHD3 and CHD4. CHD5 regulates expression of neuronal genes, cell cycle genes and remodeling genes. CHD5 is linked to regulation of genes implicated in aging and Alzheimer's disease.