Alzheimer & Parkinson

Microglia are the resident macrophages of the central nervous system¹. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult haematopoiesis^(2-4). The origins of human microglia are less clear, but recent evidence suggests that bone-marrow-derived cells contribute to the human microglial pool in certain individuals^(5-9). Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of...

Parkinson's disease (PD) is a neurodegenerative disorder involving a neuroinflammatory response, the cause of which remains unclear. Transposable elements (TEs) have been linked to inflammation, but their potential role in PD remains unexplored. Using bulk- and single-nuclei RNA-seq of postmortem brain tissue from four brain regions, we studied TE transcription and its correlation with PD neuroinflammation. Over a thousand TEs, including LINE-1 s and ERVs, were expressed in a cell type- and...

Tau pathology closely tracks neuronal loss in Alzheimer's disease, but how phosphorylated tau becomes lethal has remained unclear. Chen et al. identify a dual-hit mechanism: glucose hypometabolism removes a protective A20-mediated brake on necroptosis while phosphorylated tau scaffolds RIPK1 activation, driving tau-associated neuronal death.¹.

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Symptomatic treatment remains central to the clinical management of Alzheimer disease (AD), even as disease-targeted therapies emerge. This Review synthesizes current evidence for pharmacological and non-pharmacological symptomatic therapies targeting cognition, function and neuropsychiatric symptoms in AD. Non-pharmacological interventions, including cognitive training, physical exercise, cognitive stimulation therapy and multimodal lifestyle programmes, show small-to-moderate benefits,...

The study of Alzheimer's disease (AD)-associated mutations has implicated dysregulation of amyloid precursor protein (APP) proteolysis in the disease. Brain recordings have revealed synaptic hyperexcitation during asymptomatic and early stages of AD, reverting to overinhibition as dementia progresses. Here, we show that endogenous APP and its proteolytic C-terminal fragments (APP-CTFs), the precursors of amyloid-β (Aβ), are enriched at excitatory synapses. Pharmacological modulation of...

Damaged mitochondria are selectively eliminated through mitophagy, a critical quality control process. A kinase PINK1 and an E3 ubiquitin ligase PRKN/Parkin, both of which are mutated in familial Parkinson disease, amplify ubiquitin signals on the damaged mitochondria. The autophagy receptor OPTN plays a pivotal role in mitophagy by bridging ubiquitinated mitochondria with autophagy components. Although OPTN is known to recruit ATG9A-positive vesicles to facilitate mitophagy progression, the...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose pathological course involves amyloid-β (Aβ) deposition, tau abnormalities, neuroinflammation, and neurovascular dysfunction. Interest in the microbiota-gut-brain axis does not arise because gut dysbiosis has been established as an independent initiating cause of sporadic AD, but because this axis connects modifiable peripheral factors-including diet, medication, ageing, and intestinal physiology-with barrier homeostasis,...

Structurally diverse tau filaments form proteinaceous aggregates in a heterogeneous group of neurodegenerative diseases called tauopathies. The factors extrinsic to the highly ordered core structure that influence tau filament stability are not well understood. Here, we found that polyubiquitinated tau filaments from Alzheimer disease and vacuolar tauopathy human brain tissue exhibit distinct seeding patterns in mice, in association with differences in tau filament ultrastructure determined by...

Levodopa is the gold-standard treatment for Parkinson's disease, but chronic use results in levodopa-induced dyskinesia (LID) in approximately 80% of patients. Previous research has identified critical network changes in the cortico-basal ganglia pathway associated with LID; however, no study has extensively recorded motor thalamus single-cell activity in a LID model. The motor thalamus is a key node in the movement pathway, receiving basal ganglia and cerebellar inputs and projecting an...

Protein phase separation is a fundamental process in organizing membraneless organelles and is implicated in pathological conditions. Importantly, this process is dynamic and depends on conditions such as concentration, temperature, and solvent composition. However, current machine learning models infer phase separation propensity solely from amino acid sequences, failing to capture these context-dependent behaviors. Here we show that LLPSense, a machine learning framework that integrates...

Understanding the complex interplay between gene expression and neuronal activity is crucial for unraveling the molecular mechanisms underlying cognitive function and neurological disorders. Here, we developed pooled screens using CRISPR interference (CRISPRi) and the fluorescent calcium integrator CaMPARI2 to evaluate genetic modifiers of neuronal depolarization. Using this screening method, we evaluated 1343 genes for their effect on depolarization in a human iPSC-derived neuron model,...

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation. Dysregulation of the brain renin-angiotensin system, particularly hyperactivation of the angiotensin II type-1 receptor, contributes to AD pathogenesis. In contrast, activation of the angiotensin II type-2 receptor (AT(2)R) has been linked to neuroprotection and reduced Aβ accumulation. However, the underlying mechanisms of AT(2)R-related Aβ reduction and the role of...

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Neurons actively shape immune responses that maintain central nervous system integrity. We identify SPP1 (secreted phosphoprotein 1) as a neuron-derived signal that reprograms microglia into a neuroprotective, homeostatic state after injury and during neurodegeneration. In mouse models of glaucoma and optic nerve damage, neuronal SPP1 enhances microglial autophagy, debris clearance, and anti-inflammatory activity, preserving neuronal survival and visual function. SPP1 is elevated in neurons of...

The identification of pathogenic autosomal recessive mutations in the gene encoding the PINK1 kinase provided early evidence linking mitochondrial dysfunction to neurodegeneration - in this case Parkinson's Disease. PINK1 has since become synonymous with mitophagy, with the prevailing model proposing two alternative fates. The first being partial import - inner-membrane penetration of its transmembrane domain (TMD) - followed by PARL-mediated cleavage and degradation. This happens in healthy...

Parkinson's disease (PD) is defined pathologically by loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). Yet synaptic dysfunction emerges much earlier, making it essential to define the mechanisms that drive early nigrostriatal deregulation. In the SNc, molecularly distinct dopamine neuron subtypes show differential susceptibility to PD. Here, we used intersectional genetic mouse models to determine how the PD-linked kinase LRRK2 affects vulnerable dopamine subtypes....

Previously derived polygenic risk scores (PRSs) for Alzheimer's disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated...

Endolysosomal dysfunction is a hallmark of Alzheimer's disease and related tauopathies, yet underlying mechanisms remain poorly understood. This study investigates the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau aggregation and toxicity in Caenorhabditis elegans and human cell culture models. Fluorescence recovery after photobleaching and C-Laurdan dye imaging revealed that silencing sphingolipid metabolism genes reduced endolysosomal...

Neuroinflammation and synapse loss are associated with cognitive decline in Alzheimer's disease (AD). Although microglial hyperphagocytic activity has been implicated in synapse loss^(1-4), the mechanisms underlying these pathologies remain obscure. Here we demonstrate that, during AD progression in mice, astrocytes and microglia increase phagocytic elimination of excitatory synapses while reducing elimination of inhibitory synapses, suggesting that neuroinflammation alone may be dispensable for...