Alzheimer & Parkinson

Chaperone-mediated autophagy (CMA), regulated by its lysosomal receptor LAMP2A, is a key pathway for αSynuclein (αSyn) clearance and a direct target of αSyn-related neurotoxicity. Rodent studies show that LAMP2A enhancement reverses neurodegeneration, whereas its deficiency accelerates pathology. To test translational relevance, we examined whether increasing LAMP2A expression in nonhuman primates could mitigate α-synucleinopathy induced by injections of Parkinson's disease patient-derived Lewy...

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The human nigrostriatal pathway, comprising dopaminergic neurons in the ventral midbrain that project to the dorsolateral striatum, is essential for motor control and selectively vulnerable in Parkinson's disease. How this circuit assembles during human development remains poorly understood, and in vitro models capturing its long-range connectivity and spatial organization have been lacking. Here, we establish a compartmentalized, human stem cell-based model of the nigrostriatal pathway by...

CONCLUSIONS: Using a novel graph-based SV calling pipeline, we identify high-quality SVs across a large and ancestrally diverse cohort. Our analyses reveal both common and rare SVs associated with AD. These findings provide valuable insights into the genetic architecture of AD, emphasizing the value of including diverse populations in AD genomic studies.

In this issue of Cell, Brioschi et al. identify cellular musculoaponeurotic fibrosarcoma (cMAF) as a key regulator of brain perivascular macrophages that supports cerebrovascular function through insulin-like growth factor 1 (IGF1) production. This cMAF-IGF1 program is enhanced in Alzheimer's disease (AD), potentially reflecting a protective response that is lost in APOE4 carriers.

Alzheimer's disease (AD) is characterized by marked heterogeneity in the timing and extent of neuronal dysfunction and degeneration. Specific neuronal populations, including entorhinal cortex layer II stellate cells, hippocampal CA1 pyramidal neurons, basal forebrain cholinergic neurons, locus coeruleus noradrenergic neurons, and prefrontal parvalbumin interneurons, show different combinations of functional, pathological, and degenerative vulnerability during disease progression. The strength...

Daniali et al. show that dopamine drives mitochondrial stress, mtDNA release, and cGAS-STING-dependent IL-6 production in human macrophages. These findings suggest a mechanism linking dopaminergic signaling to mtDNA damage signatures increasingly detected in blood from patients with Parkinson's disease.

Alzheimer's disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050¹. AD is highly heritable, with twin-based heritability estimates of 60-80%². Although 1,200 causal loci are predicted to exist for AD³, approximately 80 loci have been associated with AD in two recent studies^(4,5). Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be...

Molecular profiling studies have mapped vascular alterations in Alzheimer's disease, but have not proven a role for them in pathology. Longitudinal studies are needed to link molecular and structural changes to vascular mechanics, hemodynamics, and tissue perfusion.

Although tau pathology correlates with cognitive decline in Alzheimer's disease (AD), some individuals exhibit resilience by maintaining cognitive function. The mechanisms enabling this protection, particularly before widespread cortical degeneration occurs, remain elusive. Here, we identify a dynamic interplay between cellular vulnerability and circuit-level resilience that shapes cognitive outcomes in AD. Tau accumulation in the Edinger-Westphal nucleus (EW) impairs attention by inducing...

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...

The network of transcription factors (TFs) is an integral component of executing macroautophagy/autophagy-lysosome gene expression to maintain cellular homeostasis. Across metazoans, conserved TFs, particularly the helix-loop-helix factor TFEB, convert upstream signals into specific genetic programs through mechanisms ranging from DNA recognition and chromatin remodeling to biomolecular condensates. The dysregulation of TF-governed gene programming disrupts the progression of metabolic disease...

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...