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Levetiracetam prevents Abeta production through SV2a-dependent modulation of APP processing in Alzheimer's disease models

2 weeks 6 days ago
Amyloid-β (Aβ) peptides are a defining feature of Alzheimer's disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ(42) in...
Nalini R Rao

Silencer variants are key drivers of gene up-regulation in Alzheimer's disease

2 weeks 6 days ago
The genetic mechanisms of ~90% of Alzheimer's disease (AD)-associated variants residing in noncoding DNA remain poorly understood. To address this, we developed a deep learning framework that integrates bulk histone modification data with single-cell open chromatin profiles to evaluate the regulatory potential of noncoding variants. This model identified 1457 silencer and 3084 enhancer AD-associated variants in dorsolateral prefrontal cortex, classifying gene loci as silencer-only (SL),...
Di Huang

VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and alpha-synuclein pathology in DJ-1-linked Parkinson's neurons

2 weeks 6 days ago
Parkinson's disease (PD) is characterized by α-synuclein accumulation and dopaminergic neuron degeneration, with dopamine (DA) oxidation emerging as a key pathological driver. However, the mechanisms underlying this neurotoxic process remain unclear. Using PD patient-derived and CRISPR-engineered induced pluripotent stem cell midbrain dopaminergic neurons lacking DJ-1, we identified defective sequestration of cytosolic DA into synaptic vesicles, which culminated in DA oxidation and α-synuclein...
Leonie M Heger

Advances in the multifunctional roles of CX3CL1 in the central nervous system

2 weeks 6 days ago
C-X3-C motif chemokine ligand 1 (CX3CL1), a structurally unique chemokine in the central nervous system (CNS), shapes physiological and pathological processes via specific binding to its receptor, C-X3-C motif chemokine receptor 1 (CX3CR1). Empirical evidence indicates that this signaling axis exerts dual neuroinflammatory effects: It restrains microglial hyperactivation, yet can promote inflammation under conditions such as chronic stress. Notably, it preserves synaptic plasticity and...
Yuhui Chen