Alzheimer & Parkinson

Deposition of misfolded α-synuclein (αsyn) in the enteric nervous system (ENS) is found in multiple neurodegenerative diseases. It is hypothesized that ENS synucleinopathy contributes to both the pathogenesis and non-motor morbidity in Parkinson's Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we employ a fibrillar injection model of enteric synucleinopathy in male mice and demonstrate that ENS-resident...

Emerging evidence implicates the Stuxnet (Stx) protein in human disease, extending beyond its known role in proteasome-independent degradation. Exploring this further, our investigation into stx downstream targets in Drosophila reveals that loss of the U snoRNA host gene 5 (Uhg5) gene disrupts sleep. This sleep phenotype is linked to inefficient translation of mitochondrial genes, as Uhg5 produces small nucleolar RNAs (snoRNAs) that directly regulate mitochondrial transcripts. Using GoldCLIP...

Synapses serve as the central functional components mediating information transmission, integration, and storage within the central nervous system (CNS). Their functionality depends on the synergistic interplay of the presynaptic membrane, synaptic cleft, and postsynaptic membrane-three structures that collectively sustain neurotransmitter secretion, postsynaptic signaling, and synaptic plasticity. Of note, synaptic impairment represents an early, shared pathological hallmark across aging and...

Spatial omics links molecular measurements to their positions in tissue, revealing cellular organization and interactions. Yet most computational tools highlight common cell types and overlook rare populations that can drive disease. Here we show GARDEN, a computational framework that identifies and characterizes these pathogenic cells or regions in spatial omics by embedding graph-based dynamic attention into a spatially-aware graph fusion contrastive model. GARDEN works consistently across...

Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer's disease) and alpha-synuclein in Parkinson's disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental...

Parkinson's disease (PD) is a chronic neurological disorder characterized by loss of body movement control due to dopamine abnormalities. PD leads to various pathological symptoms, including muscle stiffness, bradykinesia, tremors, and postural disturbances. As a severe disease, PD caused approximately 329,000 deaths worldwide in 2019. However, PD treatment is very challenging; thus, alternative therapeutic strategies are in high demand. The primary therapeutic hurdle in PD therapy is the...

Parkinson's Disease (PD) is a neurodegenerative disorder primarily characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to classical motor symptoms such as tremors, rigidity, and bradykinesia. In later stages, patients frequently develop non-classical symptoms, including respiratory dysfunctions, which may result from neurodegeneration in brainstem regions involved in respiratory control, such as the pre-Bötzinger Complex (preBötC) and the retrotrapezoid...

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Lysosomal and endoplasmic reticulum (ER) Ca^(2+) release mutually influence each other's functions. Recent work revealed that ER-located ryanodine receptor(s) (RyR(s)) Ca^(2+) release channels suppress autophagosome turnover by the lysosomes. In familial Alzheimer's disease, inhibiting RyR hyperactivity restored autophagic flux by normalizing lysosomal vacuolar H^(+)-ATPase (vATPase) levels. However, the mechanisms by which RyRs control lysosomal function and how this involves the vATPase remain...

Trained immunity, the long-term reprogramming of innate immune cells to elicit an enhanced response upon subsequent challenges, has become a key concept in understanding a wide range of pathologies, including both acute and chronic inflammatory disorders. Recent evidence suggests that trained immunity also plays a significant role in the development and progression of various neurological disorders and related comorbidities, in which brain pathology can lead to trained immunity. This review...

Trisomy 21 (T21) gives rise to Down syndrome (DS), the most commonly occurring chromosomal abnormality in humans. T21 affects nearly every organ and tissue system in the body, predisposing individuals with DS to congenital heart defects, autoimmunity, and Alzheimer's disease, among other co-occurring conditions. Here, using multi-omic analysis of plasma from more than 400 people, we report broad metabolic changes in the population with DS typified by increased bile acid levels and protein...

Astrocytes not only play a central role in orchestrating the brain's microenvironment but also are tightly connected to neurodegenerative processes. Hence, unraveling astrocytes' intercellular pathways can give important insight into disease-spreading mechanisms. Here, we describe a distinct form of actively migrating cellular vehicles, which we have named zombosomes. Zombosomes shed from astrocytes but retain their adhesive and motile properties, even though they lack nuclei. They share protein...

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,...

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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...