Alzheimer & Parkinson

The lysosomal cation channel TMEM175 plays a key role in luminal pH homeostasis and lysosome function, with aberrant activity linked to Parkinson's disease. Although initially described as a K^(+)-selective channel, TMEM175 exhibits substantial H^(+) permeability. Here, we dissect complex changes affecting human TMEM175 conductance and ionic properties of TMEM175-mediated current in response to pH shifts on the luminal side of the protein. A drop in pH from 7.4 to 4.7 on the side equivalent to...

Disruption of the blood-brain barrier (BBB) increases vascular permeability and promotes neuroinflammation, contributing to Alzheimer's disease (AD) progression. However, the molecular drivers of BBB dysfunction and neuroinflammation in AD remain poorly defined. Here, we identify angiopoietin-2 (ANGPT2) as a central mediator of BBB breakdown and AD progression. Transcriptomic analyses of human AD brains revealed elevated ANGPT2 expression in endothelial cells correlating with disease severity....

The zebrafish (Danio rerio) is a powerful vertebrate model for studying neurodegenerative diseases and regenerative medicine due to its genetic similarity to humans and its unique ability to regenerate the central nervous system (CNS). This review synthesizes key findings on zebrafish neural regeneration across the retina, spinal cord, and brain, emphasizing translational relevance. Zebrafish effectively model disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, stroke,...

No abstract

Synaptic vesicle glycoprotein 2A (SV2A), a transmembrane protein widely localized to synaptic vesicles, serves as a key indicator of synaptic loss in Alzheimer's disease (AD). In this study, adeno-associated virus (AAV) was injected by brain stereotactic injection technique to construct SV2A-overexpressing APP/PS1 mice, then the effects of SV2A on amyloid precursor protein (APP) degradation and its molecular mechanism were further explored in vivo or in vitro. Our results demonstrated that SV2A...

CONCLUSIONS: AD management requires a systems-oriented therapeutic architecture in which interventions are selected based on mechanistic dominance, biomarker stage, and potential synergy. We outline a multi-target strategy integrating amyloid/tau modulation, neuroimmune regulation, metabolic-vascular stabilization, and synaptic support. Future work should prioritize biomarker-guided stratification, treatment sequencing, and prevention-oriented combination designs.

Apoptosis, a programmed cell death process activated in Alzheimer disease (AD), is not limited to neurons but extends to all cell types within the central nervous system (CNS). However, how apoptotic cells mediate their impact on surrounding cells and contribute to the pathological progression of AD remains largely unclear. Here, we report that in 5×FAD mice, cells surrounding amyloid-β (Aβ) plaques undergo apoptosis, which occurs concurrently with elevated macroautophagy/autophagy. The...

Neurodegenerative diseases are characterized by a gradual loss of neurons, cellular dysfunction, loss of intricate synaptic networks and brain damage, which are going to be the second leading cause of death in future. These proteinopathies are marked by abnormal amyloid fibril deposition, aberrant aggregation of misfolded proteins via polymerization, where protein aggregates serve as key pathological hallmarks in Alzheimer's, Parkinson's, and multiple system atrophy disorders. These toxic...

Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders, including Alzheimer's disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder enlargement, and lipid dyshomeostasis. To better understand the relationship between neuroinflammation...

Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most prevalent type of dementia characterized by pathological deposition of amyloid-β plaques/deposits and tau tangles within the brain parenchyma. This progressive ailment is featured by irreversible cognitive impairment and memory loss, often misdiagnosed as the consequence of old age in elderlies. Pathologically, synaptic dysfunction occurs at the early stages and then progresses into neurodegeneration with neuronal...

Deposition of amyloid proteins and their associated interactome is a hallmark of Alzheimer's disease (AD) and other amyloidosis diseases, with their composition implying disease etiology. However, precise in-situ micro-dissection of amyloid deposits in AD brain tissue remains a challenge. In this work, we first divert the excited state energy of Thioflavin T from singlet fluorescence to triplet photocatalytic amyloid protein labeling through molecular engineering, while maintain its pan-amyloid...

Freezing of gait (FOG) is among the most debilitating symptoms of Parkinson disease and related disorders, often resulting in falls and a loss of independence. FOG has an episodic and heterogeneous nature that makes it difficult to measure and treat. The field currently lacks a consensus on how to precisely define this phenomenon. For this reason, the International Consortium for Freezing of Gait convened a group of experts to establish an updated 'clinical' definition of FOG for use in the...

Epigenetic mechanisms, including histone acetylation, regulate learning and memory and underlie Alzheimer's disease and related dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme generating acetyl-CoA, locally regulates histone acetylation and gene expression in neuronal nuclei. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously, we showed that systemic ACSS2 knockout mice, although largely normal in physiology,...

Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both...

Alzheimer's drug developer accuses companies it hired of providing "medically impossible" results.

Single-cell transcriptomic studies have identified distinct microglial subpopulations with shared and divergent gene signatures across development, aging, and disease. Whether these microglial subsets represent ontogenically separate lineages of cells or are manifestations of plastic changes in microglial states downstream of some converging signals is unknown. Furthermore, despite the well-established role of enhancer landscapes underlying the identity of microglia, the extent to which histone...

As a pathological hallmark of Parkinson's disease (PD), a-synucleinopathy induces various cellular damages, including calcium overload, mitochondrial and autophagic dysfunction, ultimately resulting in dopaminergic neuron death. However, the hierarchy of these detrimental events remains unclear. It is well established that a-synuclein can induce calcium overload through diverse mechanisms. To assess whether calcium overload plays a crucial detrimental role, we established a calcium overload...

Somatic variants are increasingly recognized as contributors to diverse non-cancer, developmental, and aging-related disorders. However, most tools for detecting somatic single-nucleotide variants (sSNVs) were designed for DNA sequencing and primarily tailored to cancer datasets, leaving a critical gap in harnessing the rich potential of RNA-seq for sSNV identification, particularly in non-cancer tissues with low mutation rates. Here, we introduce RNA-MosaicHunter, a novel bioinformatic tool for...

Parkinson's disease (PD) is a progressive neurodegenerative disease that casts a significant shadow over global health and the identification of therapeutic targets for PD will empower more effective clinical treatment. The gene encoding the deubiquitinating enzyme USP25 has been identified as a susceptible locus for PD, but the role of USP25 in PD remains unknown. In this study, we found that USP25 exacerbated dopaminergic neuronal loss and motor deficits in murine models of PD by sabotaging...

TAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of several neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease. Although cryptic exon inclusion is a well-characterized consequence of TDP-43 loss of function, emerging evidence reveals broader roles in RNA metabolism, notably in the regulation of alternative polyadenylation (APA) of disease-relevant transcripts. In the present study, we examined 3' untranslated region...