Alzheimer & Parkinson

Parkinson's disease involves progressive α-synuclein pathology, but how this reshapes the brain's spatial immunometabolic landscape, and how oligodendrocytes participate, remain incompletely defined. Here we combine single-nucleus RNA sequencing, spatial transcriptomics and spatial metabolomics in male A53T α-synuclein transgenic mice across disease stages, together with male mice carrying adeno-associated virus-mediated α-synuclein overexpression, human midbrain and cerebrospinal fluid samples....

The selective loss of dopaminergic neurons in the substantia nigra pars compacta is a defining feature of Parkinson's disease (PD), yet its underlying mechanisms remain unclear. NUS1, which encodes neurite outgrowth inhibitor-B receptor (NgBR), was recently identified as a PD risk gene. Here we show that NgBR is highly expressed in microglia, where its deficiency drives progressive PD-like motor deficits and dopaminergic neurodegeneration via the LCN2-SLC22A17 iron-transport axis in mice. NgBR...

Aging, neuroinflammation and metabolic dysfunction are tightly intertwined in Alzheimer's disease (AD), but how transient pathological signals become persistent cellular states remains poorly understood. Histone post-translational modifications (PTMs) provide a dynamic interface between extracellular stimuli, cellular metabolism and chromatin state. This Review examines how canonical histone modifications and emerging metabolite-derived acylations regulate inflammatory and stress-responsive...

High-quality reference genomes are essential for comparative and functional genomics yet remain unavailable for many emerging model organisms. Here, we report OctDeg2.0, a chromosome-level genome assembly and annotation of the degu (Octodon degus), generated using PacBio HiFi long-read sequencing and Hi-C scaffolding from a single male individual. Octodon degus is of growing interest as a natural animal model for aging and Alzheimer's disease research. The 3.4 billion base-pair assembly...

Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of...

Neurodegenerative diseases are emerging as an important consequence of population ageing in sub-Saharan Africa (SSA), but their scientific relevance extends beyond a projected rise in case numbers. SSA combines exceptional human genomic diversity with marked heterogeneity in vascular and metabolic risk, infection, nutrition, occupational exposures, air pollution, and access to health care. This combination creates an underused setting in which to study why biological ageing produces...

Blood phosphorylated tau 217 (p-tau217) accurately detects Alzheimer's disease (AD) pathology but is also elevated in amyotrophic lateral sclerosis (ALS), likely reflecting peripheral (big) tau released from muscle. Assays selectively measuring brain-derived (BD-) tau and BD-p-tau217 are therefore needed. We analysed serum BD-tau and p-tau217 in ALS (n = 139), AD (n = 101) and controls (n = 75) using direct immunoassays and after BD-Tau immunoprecipitation (BD-Tau-IP), and tau species in brain...

The RNA-binding protein T cell intracellular antigen-1 (TIA1) regulates cellular stress responses and tau pathology, key contributors to the pathophysiology of tauopathies, including Alzheimer's disease (AD). TIA1 acts in peripheral monocytes to inhibit inflammation, but its function in central microglia, critical to neuroinflammation and disease progression, remains unknown. Here, we crossed TIA1 microglial conditional knockout (cKO) mice (using a Cx3cr1-driven Cre element) with the PS19 P301S...

Pathological accumulation of MAPT/tau protein is a defining feature of Alzheimer disease (AD) and related tauopathies, highlighting the need to identify druggable regulators of MAPT/tau clearance. Using Drosophila behavioral assays focused on cytoskeletal remodeling pathways dysregulated in AD, we identified genes whose genetic modulation mitigates MAPT/tau-induced behavioral deficits. These modifiers were validated by histopathology and mechanistically examined in human tauopathy cell models to...

There is little causal evidence on factors that can protect individuals against Alzheimer's Disease and Related Dementias (ADRD) risk. We study the causal effect of education on ADRD, exploiting a regression discontinuity generated by a compulsory schooling reform. ADRD was ascertained based on medical history, hospital records, and death registries, addressing concerns about selective sample attrition. We find that education reduces incidence of ADRD. Using molecular genetic data, we show that...

In Alzheimer's disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway promotes microglial neuroprotective functions by engaging multiple cell receptors. However, the relevant downstream effectors are not fully understood. mTOR complex 1 (mTORC1) promotes mRNA translation by phosphorylating and inactivating eukaryotic translation initiation factor 4E-binding protein 1 and 2 (4E-BP1/2), which are expressed in microglia. 4E-BP1 levels in cerebrospinal fluid (CSF) are...

Retrospective studies in patients with nonmuscle invasive bladder cancer have reported a significant reduction in Alzheimer's disease incidence (12 to 78%) among Bacille Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-magnetic resonance Imaging (MRI)...

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Epidemiological studies link kidney function to Parkinson's disease risk, but the genetic basis of this relationship remains unclear. Here, we leverage genome-wide association data for Parkinson's disease and five UK Biobank-derived kidney-related traits in individuals of European ancestry, combining genetic correlation, pleiotropy mapping, colocalization and enrichment across sex-combined and sex-stratified analyses. Genome-wide genetic correlations with Parkinson's are modest, with only a...

Although brain cholesterol dysregulation is implicated in Parkinson's disease (PD), targeting cholesterol synthesis has shown limited efficacy. Here we identify ATP-binding cassette transporter A1 (ABCA1) as a critical regulator of cholesterol homeostasis in PD. We show that ABCA1 expression is elevated in the substantia nigra of postmortem PD brains and in a PD mouse model, with regional analyses revealing preferential alterations in nigral and striatal circuits. Mechanistically, astrocytic...

Blood biomarkers are transforming Alzheimer's disease diagnostics by enabling a scalable, minimally invasive assessment of pathology. Food and Drug Administration clearances and European market certifications of different plasma tests mark a shift toward biological diagnosis in routine care. However, clinical implementation is not guided by diagnostic accuracy alone but will depend on improved patient-centered and pathway-level outcomes, including diagnostic confidence, the appropriate use of...

Genetic evidence implicates immune dysfunction in Alzheimer's disease (AD), yet the neuroimmune mechanisms operating in human tissue remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates human induced pluripotent stem cell-derived microglia and CD8^(+) T cells to reconstitute multicellular AD pathology. This system enables functional interrogation of both innate and adaptive immune components in a human-relevant context. Using this...

Multiple lysosomal stresses activate Parkinson's-linked LRRK2 kinase, and these involve the so-called "CASM" pathway to help recruit LRRK2 to lysosome surfaces. Clegg et al. (https://doi.org/10.1083/jcb.202511137) show that LRRK2, activated upon lysosome swelling caused by PIKfyve inhibition, instead relies solely on Rab GTPase binding for lysosome localization and activation.

Increased activity of leucine-rich repeat kinase 2 (LRRK2) confers Parkinson's disease risk. LRRK2 dynamically localizes to lysosomal membranes in response to various stresses, yet the mechanisms by which distinct lysosomal perturbations are communicated to LRRK2 remain unclear. Here, we show that inhibition of the lysosomal lipid kinase PIKfyve promotes LRRK2 recruitment and signaling through a pathway that requires the lysosomal chloride/proton antiporter ClC-7. ClC-7 in turn controls the...

Immune-neuron interactions play a critical role in neuroinflammatory and neurodegenerative diseases, such as Alzheimer's disease (AD), but how CD8⁺ T cells contribute to brain pathology remains poorly understood. Amyloid-β (Aβ), a hallmark of AD, is known to trigger neuronal stress and inflammation. Here, we established a human cortical organoid (hCO) model to investigate CD8⁺ T cell responses to Aβ-induced neurodegenerative stress. Aβ exposure increased neuronal expression of CX3CL1...