Alzheimer & Parkinson

Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains...

Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8^(+) T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8^(+) T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen...

Plasma pTau217 is a leading biomarker for Alzheimer's disease, but evidence from genetically admixed populations in low- and middle-income countries remains limited. We evaluated the diagnostic performance of pTau217 and pTau217/Aβ42 measured using Simoa technology in memory-clinic cohorts from Brazil (Cog-Aging-Study, n = 353) and Argentina (GeNED.ar, n = 134). Here we show that both biomarkers accurately identified cerebrospinal fluid (CSF)-defined amyloid pathology in Cog-Aging-Study-Brazil...

BACKGROUND: As individuals with Down syndrome age, they face high risks of Alzheimer's disease and epilepsy. With symptomatic Alzheimer's disease, late-onset myoclonic epilepsy in Down syndrome (LOMEDS) often emerges. We aimed to examine how epilepsy develops in Down syndrome, its timing relative to Alzheimer's disease symptom onset, and its effect on prognosis.

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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...