Alzheimer & Parkinson

A growing body of evidence supports the contribution of the long-lasting adaptive immune system in Parkinson's disease (PD). We showed that the PD-associated protein PINK1 negatively regulates the presentation of mitochondrial antigens (MitAP) on MHC-I molecules. In vivo evidence indicated that MitAP activation in mice, in the absence of PINK1, led to cytotoxic CD8^(+) T cell stimulation and severe motor impairments, reversible by L-DOPA. We show here that following TLR4 activation, MitAP is...

Amyloid precursor protein (APP) is widely known for its role in Alzheimer's disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological functions remain incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell...

Alzheimer's disease (AD), characterized by progressive cognitive decline, represents a major public health challenge in aging societies. Since the proposal of the amyloid cascade hypothesis, Aβ-targeted therapeutic strategies have dominated this field for over three decades. Although recent anti-Aβ antibodies have shown modest promise, their limited clinical benefits coupled with safety concerns underscore the necessity of re-evaluating the pathological mechanisms underlying AD. Cerebral...

The cerebellum contains most of the brain's neurons and supports many functions, yet how it changes with age remains unclear. Here we used three brain imaging studies spanning 47,000 adults and examined how different parts of the cerebellum age and their relation to cognition. We characterized cerebellar aging using volumetry and the T1-weighted/T2-weighted ratio, and corroborated these findings with quantitative magnetic resonance imaging in an independent sample. We show a spatially...

Restoring striatal dopamine synthesis is a promising gene therapy strategy for Parkinson's disease. Previous adeno-associated virus-mediated aromatic L-amino acid decarboxylase (AADC) monotherapies remain dependent on exogenous levodopa, whereas multigene delivery is constrained by strict adeno-associated virus packaging limits. A 'dual approach' targeting the two rate-limiting enzymes, tyrosine hydroxylase (TH) and AADC, offers the potential for autonomous dopamine synthesis. We report the...

Altered astrocyte-microglia interactions have been implicated in the pathogenesis of Alzheimer's disease, but the underpinning mechanisms remain unclear. Zhang and colleagues show that astrocytic PAD2-mediated citrullination of vimentin activates microglia, worsens Aβ accumulation, and exacerbates cognitive deficits. These findings highlight astrocyte-microglia crosstalk as a potential therapeutic target for Alzheimer's disease.

Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative...

The perivascular glymphatic system promotes cerebrospinal fluid-interstitial fluid (CSF-ISF) interaction and macromolecular waste clearance and is an important determinant of brain homeostasis, the performance of which deteriorates with age. Astrocyte biology, vascular integrity, and age-associated cerebrovascular dynamic alterations interfere with the polarization of aquaporin-4 (AQP4) water channels on astrocytic endfeet, decreasing the clearance of aggregation-prone proteins, such as...

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in preclinical models of neurodegeneration, with emerging evidence suggesting these effects may be driven by modulation of neuroinflammation. However, the cellular mechanisms underlying GLP-1RA effects on neuroinflammation remain poorly understood. Here we show, using a mouse model of lipopolysaccharide-induced neuroinflammation, how semaglutide coordinates cellular responses to resolve neuroinflammation. We find that...

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Alzheimer's disease (AD) is a devastating neurodegenerative disorder marked by progressive cognitive decline. Metabolic disruptions are widely observed, yet their involvement in the molecular aetiology of AD remains underexplored. Here we identify hyperglycosylation as a driver of AD. Integrating spatial metabolomics, lipidomics and glycomics in transgenic AD mouse models and post-mortem human AD samples, along with advanced spatial isotopic tracing pulse-chase analysis of N-linked glycans, we...

Lewy bodies, the defining pathological feature of Parkinson's disease, are intraneuronal inclusions enriched in aggregated alpha-synuclein (αSyn). We used correlative light and electron microscopy to selectively investigate phosphorylated αSyn (αSyn^(pS129))-positive inclusions in the substantia nigra of end-stage postmortem Parkinson's disease brain. Here we show that somatic αSyn^(pS129) inclusions in nigral dopaminergic neurons are consistently fibrillar, whereas the membranous-type...

An increasing number of studies indicate that ferroptosis, a lethal pathway initiated by excessive iron-dependent lipid peroxidation, and pivotal to the survival of dopaminergic neurons and the progression of Parkinson's disease (PD), may be regulated by the lysosomal pathway. Mutation and loss of function of the lysosomal enzyme, glucocerebrosidase, induce the accumulation of glycosphingolipids and alterations in lysosome activity, which have been associated with a higher risk of developing PD....

α-synuclein (α-syn) aggregation is a hallmark of synucleinopathies, a class of neurodegenerative disorders such as Parkinson's disease (PD). Several lines of evidence indicate the involvement of mitochondria in the disease pathology. Despite extensive study, the link between α-syn aggregation and mechanisms of mitochondrial toxicity remains not fully understood. Using high-resolution imaging with electron microscopy, we examined SH-SY5Y cells exposed to α-syn fibrils vs control cells with a...

Lysosomal defects are closely linked to Parkinson's disease (PD). Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are major genetic risk factors for PD. GBA1 deficiency causes lysosomal dysfunction, leading to α-synuclein (α-syn) accumulation and PD progression. However, the underlying mechanisms remain unclear. In this study, we identified a novel GBA1-KAT8 regulatory pathway that controls lysosomal activity. GBA1 overexpression enhances lysosomal enzyme...

Artificial Intelligence (AI) has become integral to the research of neurological diseases due to the rapid expansion of neuroimaging, clinical, physiological, and wearable data. However, the concise synthesis of recent machine learning (ML) and deep learning (DL) remains limited. This systematic review analyzes studies published between January 2021 and March 2026 on five major conditions- Alzheimer's disease, stroke, Parkinson's disease, brain tumors, and traumatic brain injury (TBI)-following...

Parkinson's disease (PD) is a neurodegenerative disease affecting the central nervous system with effects on the skeletal muscle that entails detailed characterization. Several PD-associated motor symptoms, such as rigidity, movement delays and postural instability, involve the skeletal muscle. We used the human α-syn A53T mutant mouse model to characterize the PD-associated skeletal muscle abnormalities. These mice exhibit reduced muscle weight, myofiber size and grip strength at PD onset. Gain...

Advanced amyloid beta (Aβ) pathology is associated with aberrant neuronal network activity and cognitive impairment in preclinical Alzheimer's disease (AD) models. Here, we assess Aβ pathology's impact on spatial information processing in the medial entorhinal cortex (MEC) of 18-month App^(NL-G-F/NL-G-F) knock-in (APP KI) mice during exploration of open field arenas. Spatial information scores are decreased in APP KI MEC neurons versus age-matched controls. Border cell firing preferences are...

The mechanism(s) causing selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) remain largely elusive. To improve our understanding of mitochondrial involvement and related pathways suggested to play a role in this selective vulnerability, we used tyrosine hydroxylase (TH)-mCherry reporter-induced pluripotent stem cells generated by CRISPR/Cas9. We sorted neurons into pure TH-positive and TH-negative neurons upon differentiation into a dopaminergic neuron-containing cell...

Microglia play crucial roles in Alzheimer's disease (AD), yet the molecular mechanisms are unclear. Here, we show that CD31, a recognized endothelial marker, is predominantly expressed in microglia but not in neurons or astrocytes, and it is significantly elevated in the brains of AD patients and mouse models. Microglia-specific CD31 knockdown in 5xFAD mice substantially attenuated the dysregulated transcription networks, suppressed microglia hyperactivation and the disease-associated microglia...