Alzheimer & Parkinson

How microglia digest Alzheimer's fibrillar amyloid-beta (Aβ) plaques that are too large to be phagocytosed is not well understood. Here, we show that primary microglial cells create acidic extracellular compartments, lysosomal synapses, on model plaques and digest them with exocytosed lysosomal enzymes. This mechanism, called digestive exophagy, is confirmed by electron microscopy in 5xFAD mouse brains, which shows that a lysosomal enzyme, acid phosphatase, is secreted toward the plaques in...

CONCLUSION: Our study elucidated the initiating factors and three independent pathways involved in the conversion of MCI to AD. The predictive value of each factor was clarified and a multi-predictor nomogram was established with high accuracy.

In this issue of Cell Stem Cell, Shen et al. investigate in vivo transient expression of Yamanaka factors (YFs) during embryogenesis and an adult mouse model of Alzheimer's disease (AD)-associated amyloidosis. These studies demonstrate that transient induction of YFs may be capable of enhancing neurogenesis and offer resilience against neurodegeneration.

MicroRNAs (miRNAs) play a crucial role in regulating gene expression and influence many biological processes. Despite their importance, understanding of how genetic variation affects miRNA expression in the brain and how this relates to brain disorders remains limited. Here we investigated these questions by identifying microRNA expression quantitative trait loci (miR-QTLs), or genetic variants associated with brain miRNA levels, using genome-wide small RNA sequencing profiles from dorsolateral...

Carling et al. report that late-onset Alzheimer's disease (LOAD) risk alleles drive cellular senescence, a hallmark of aging, in a tau- and sex-dependent manner. Mechanistic insights into interactions among genetic risk, biological aging, and sex differences in LOAD are presented.

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Hidden confounding biases hinder identifying causal protein biomarkers for Alzheimer's disease in non-randomized studies. While Mendelian randomization (MR) can mitigate these biases using protein quantitative trait loci (pQTLs) as instrumental variables, some pQTLs violate core assumptions, leading to biased conclusions. To address this, we propose MR-SPI, a novel MR method that selects valid pQTL instruments using Leo Tolstoy's Anna Karenina principle and performs robust post-selection...

Alzheimer's disease, a progressive neurodegenerative pathology, is characterized by the accumulation of Amyloid-β plaques in the brain. Lecanemab (BAN2401), a humanized IgG1 monoclonal antibody, binds with high affinity to Amyloid-β protofibrils. It is the first monoclonal antibody for Alzheimer's disease to receive full FDA approval. This systematic review, conducted meticulously, examines the current use and safety of Lecanemab in treating Alzheimer's disease. We screened literature from...

DLG3, also known as Synapse-associated protein 102 (SAP102), is essential for the organization and plasticity of excitatory synapses within the central nervous system (CNS). It plays a critical role in clustering and moving key components necessary for learning and memory processes. Mutations in the DLG3 gene, which result in truncated SAP102 proteins, have been associated with a range of neurological disorders, including X-linked intellectual disability (XLID), autism spectrum disorders (ASD),...

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The role of microglia in the amyloid cascade of Alzheimer's disease (AD) is debated due to conflicting findings. Using a genetic and a pharmacological approach we demonstrate that depletion of microglia before amyloid-β (Aβ) plaque deposition, leads to a reduction in plaque numbers and neuritic dystrophy, confirming their role in plaque initiation. Transplanting human microglia restores Aβ plaque formation. While microglia depletion reduces insoluble Aβ levels, soluble Aβ concentrations stay...

Plasma membrane protein degradation and recycling are regulated by the endolysosomal system, wherein endocytic vesicles bud from the plasma membrane into the cytoplasm and mature into endosomes and then degradative lysosomes. As such, the endolysosomal system plays a critical role in determining the abundance of proteins on the cell surface and influencing cellular identity and function. Highly polarized cells, like neurons, rely on the endolysosomal system for axonal and dendritic...

Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models in vivo and in vitro. ISG15 overexpression in cells...

Amyloid β (Aβ) forms aggregates in the Alzheimer's disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether Aβ also regulates glial physiology in the normal brain, however, has remained unclear. In this article, we describe the discovery of a novel signaling pathway activated by the monomeric form of Aβ in vitro that plays essential roles in the regulation of microglial activity and the assembly of...

Alzheimer's disease (AD) is the most common type of dementia which affects over than 60 million cases worldwide with higher incidence in low and middle-income countries by 2030. Based on the multifactorial nature of AD different risk factors are linked to the condition considering the brain's β-amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) as its primary hallmarks. Lately, viral photogenes specially after recent SARS-CoV-2 pandemic has gained a lot of attention in promoting the...

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a...

MicroRNAs (miRNAs), referring to a type of non-coding RNAs functioning in various biological processes, participate in the pathophysiology of Alzheimer's disease (AD) through increasing amyloid-beta (Aβ) production, enhancing Tau phosphorylation, and inducing neuroinflammation. Meanwhile, extracellular vesicles (EVs) have been suggested as promising carriers of AD biomarkers as they possess the ability to transmit information from cerebral tissue to peripheral blood. Inspired by the above...

GPR6 is an orphan G protein-coupled receptor with high constitutive activity found in D2-type dopamine receptor-expressing medium spiny neurons of the striatopallidal pathway, which is aberrantly hyperactivated in Parkinson's disease. Here, we solved crystal structures of GPR6 without the addition of a ligand (a pseudo-apo state) and in complex with two inverse agonists, including CVN424, which improved motor symptoms in patients with Parkinson's disease in clinical trials. In addition, we...

Portable, low-field magnetic resonance imaging (LF-MRI) of the brain may facilitate point-of-care assessment of patients with Alzheimer's disease (AD) in settings where conventional MRI cannot. However, image quality is limited by a lower signal-to-noise ratio. Here, we optimize LF-MRI acquisition and develop a freely available machine learning pipeline to quantify brain morphometry and white matter hyperintensities (WMH). We validate the pipeline and apply it to outpatients presenting with mild...

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