Alzheimer & Parkinson

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...

Neurodegenerative diseases, such as Mild Cognitive Impairment (MCI) and Alzheimer's, pose significant challenges due to their progressive nature and late diagnosis. Early detection remains difficult, particularly when using conventional machine learning approaches that fail to capture complex spatial and temporal patterns in multimodal clinical data. Motivated by the need for accurate, scalable, and clinically applicable diagnostic tools, this study proposes a hybrid deep learning framework...

Protollin, a nasal adjuvant, was evaluated in a randomized double-blind phase 1 study of 16 early Alzheimer's disease (AD) patients to determine safety and to assess its immunomodulatory effects. In a double-blind dose escalation study, subjects received nasal Protollin at doses of 0.1 mg, 0.5 mg, 1.0 mg, and 1.5 mg or placebo twice over a two-week period. Treatment was well-tolerated with minimal side effects. Transcriptomic and single-cell analyses demonstrated that prior to treatment, AD...

Here, we review the history, advancements, and broad utility of the NTR/prodrug system, and suggest future strategies for developing versatile ablation models. As a chemogenetic tool, the nitroreductase (NTR)/prodrug system enables precise spatiotemporal control over cell ablation. The technology leverages bacterial NTR enzymes (e.g. nfsB) to convert inert prodrugs into cytotoxic agents, thereby allowing researchers to induce targeted cell death. Although the NTR/prodrug approach was first...

Whether new neurons contribute to human cognition in old age remains debated. Recently in Cell Stem Cell, Tosoni et al.¹ show that immature-neuron transcriptional programs persist in the aged dentate gyrus and that their molecular state, not simply their abundance, tracks Alzheimer's pathology and cognitive resilience.

Impairments in axonal transport have been implicated in the pathogenesis of tauopathies, including frontotemporal dementia and Alzheimer's disease, yet the underlying mechanisms and reversibility of these deficits are largely unknown. In particular, the impacts of tau mutations, phosphorylation and aggregation on axonal transport in vivo remain controversial. By using two-photon imaging of axonal transport of BDNF granules in the mouse cortex, we reveal that deficits in axonal transport arise in...