Alzheimer & Parkinson

Genetically altered astrocytes reduce a cardinal pathological feature of Alzheimer's disease.

MS4A4A and MS4A6A are microglia-expressed genes linked to Alzheimer's disease risk. In this issue of Neuron, Rosner et al.¹ show that these proteins cooperatively restrain TREM2 signaling, dampening protective microglial responses and highlighting MS4A inhibition as a potential strategy to rejuvenate the brain's innate immune system in Alzheimer's disease.

Lewy bodies, a pathological hallmark of Parkinson's disease, are α-synuclein-enriched cytoplasmic inclusions that drive progressive neurodegeneration. A long-standing yet unmet goal has been the visualization of α-synuclein (α-Syn) inclusions in live brain and measurements of their pathological effects on individual neurons. Here, we developed genetically encoded reporters and knock-in mouse lines to achieve this goal. The reporters exhibited a 5-fold increase in fluorescence upon incorporation...

Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and...

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse...

Young-onset Parkinson's disease (PD), the most common autosomal recessive familial PD, is caused by gene mutations in Parkin (PRKN). These mutations result in Parkin protein loss and reduced enzymatic activity, leading to severe degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Adeno-associated virus (AAV) gene therapy can directly address the cause of PRKN-PD by expressing Parkin protein at levels comparable to those observed in healthy humans. AAV9...

Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function and is implicated in Alzheimer's disease (AD) pathogenesis. Here we conducted a phase 2, randomized, double-blind, placebo-controlled trial of a humanized TREM2 agonistic monoclonal antibody in 381 participants with early AD. Participants were randomized (1:1:1:1) to receive AL002 (15 mg kg^(-1), 40 mg kg^(-1) or 60 mg kg^(-1)) or placebo intravenously every 4 weeks for 48-96 weeks. AL002 demonstrated...

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Clearance of aberrant cerebral amyloid-β (Aβ) deposits represents a promising therapeutic strategy for Alzheimer's disease (AD), yet current anti-Aβ immunotherapy raises safety concerns due to frequent adverse effects. Extracellular targeted protein degradation (eTPD) offers an approach for safe and efficient clearance of disease-causing proteins. Here, we develop a next-generation eTPD platform, synthetic peptide-programmed lysosome-targeting chimeras (SPYTACs), using entirely synthesized...

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Parkinson's disease (PD) is a prevalent neurodegenerative disorder predominantly affecting individuals over 60. Its motor symptoms stem from the deterioration of dopaminergic neurons within the substantia nigra. Despite aging being a significant risk factor, the specific mechanisms linking aging and PD pathology remain unclear. Leveraging advancements in single-cell genomics, this study utilizes single-nucleus multiome sequencing to capture transcriptomic and epigenetic profiles from 40,125...

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet effective preventive or therapeutic strategies remain limited. A hallmark of AD pathology is the accumulation of insoluble amyloid-β (Aβ) aggregates, which are targeted by recent antibody-based therapies. Conversely, soluble amyloid precursor protein-alpha (sAPPα), a non-amyloidogenic cleavage product of APP, possesses neuroprotective, neurotrophic, and synaptogenic properties, and the ability to enhance memory. This...

Alzheimer's disease (AD) brains have variable neuropathologic and biochemical changes. Capturing epigenetic factors associated with this variability can reveal novel biological insights into AD pathophysiology. Here, we conduct an epigenome-wide association study of DNA methylation in 472 AD brains with neuropathologic and biochemical brain protein levels core to AD pathogenesis. Using a novel regional methylation (rCpGm) approach, we identify 5478 significant associations, 99.7% of which...

Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity weakens, contributing to decline in RNA homeostasis and disrupting essential cellular functions, including mitochondrial oxidative phosphorylation, genome stability, and immune regulation, and in turn accelerating tissue and organ dysfunction. Evidence from senescent cells, aged...

Exercise confers cognitive benefits in Alzheimer's disease (AD), yet the underlying mechanisms remain incompletely understood. Skeletal muscle functions as an endocrine organ that secretes myokines which affect the homeostasis of extra-muscular organs, including the brain. Here we found that swimming exercise promotes secretion of skeletal muscle-derived extracellular vesicles (SKM-EVs), which are subsequently taken up via pinocytosis by microglia. Gain-of-function and loss-of-function...

CONCLUSIONS: We identified genetic variants associated with increased risk of postoperative delirium. We also found evidence of shared genetic liability with Alzheimer's disease via APOE, complementing recent large-scale studies in all-cause delirium. If validated, the findings have potential clinical applications, including preoperative risk stratification and early identification of pre-clinical Alzheimer's disease risk.

Phosphorylated-tau 217 (pTau217) is currently the most promising blood-based biomarker for accurately detecting Alzheimer's disease (AD) pathology. However, interference from peripheral tau species in the kidneys or peripheral nerves can hinder diagnostic precision. Recently developed brain-derived pTau217 (BD-pTau217) assays emerge as highly specific tools for detecting AD-related pathological changes in the brain. In this study, we conducted a head-to-head comparison of the NULISAqpcr...

Circadian rhythm disruption is recognized as a feature of aging and neurodegenerative disease, yet whether intrinsic cellular circadian properties relate to underlying processes in humans remains unknown. We measured intrinsic circadian period and its deviation from 24 h (Δ-period) using ex vivo bioluminescence in dermal fibroblasts from 135 older adults with cognitive complaints. Associations with plasma biomarkers (pTau-217, neurofilament light chain [NfL], and glial fibrillary acidic protein...

The prevailing view frames microglia and macrophages as guardians against amyloid beta (Aβ) accumulation in Alzheimer's disease (AD). Here, we overturn this paradigm by demonstrating that human phagocytic cells, including differentiated THP-1 macrophages and hESC-derived microglia, are not merely passive responders but active producers of extracellular, seeding-competent Aβ42 fibrils, the amyloid species most strongly linked to parenchymal plaque formation and neurodegeneration. These...

N-bridged [3.2.1]octanes (tropanes) and their related bridged bicyclic systems constitute highly sought-after scaffolds in drug discovery and development. Notably, the enantioselective synthesis of chiral 3-aryltropanes which are compounds widely distributed across bioactive pharmaceutical agents remains underdeveloped. Tropinone is a readily available and cost-effective starting material. By initiating the synthesis from tropinone, it is possible to substantially lower the synthesis costs. Here...