Alzheimer & Parkinson

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This study conducted exploratory analyses of the effects of BIIB080, a MAPT (microtubule-associated protein tau)-targeting antisense oligonucleotide, in participants with mild Alzheimer's disease. A multicenter, randomized, double-blind, phase 1b trial was conducted as a placebo-controlled, multiple-ascending dose (MAD) study followed by an open-label, long-term extension (LTE). During the MAD study, participants were randomized and received either intrathecal placebo or BIIB080 10 mg (n = 6),...

Amyloid-β (Aβ) peptides are a defining feature of Alzheimer's disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ(42) in...

The genetic mechanisms of ~90% of Alzheimer's disease (AD)-associated variants residing in noncoding DNA remain poorly understood. To address this, we developed a deep learning framework that integrates bulk histone modification data with single-cell open chromatin profiles to evaluate the regulatory potential of noncoding variants. This model identified 1457 silencer and 3084 enhancer AD-associated variants in dorsolateral prefrontal cortex, classifying gene loci as silencer-only (SL),...

Parkinson's disease (PD) is characterized by α-synuclein accumulation and dopaminergic neuron degeneration, with dopamine (DA) oxidation emerging as a key pathological driver. However, the mechanisms underlying this neurotoxic process remain unclear. Using PD patient-derived and CRISPR-engineered induced pluripotent stem cell midbrain dopaminergic neurons lacking DJ-1, we identified defective sequestration of cytosolic DA into synaptic vesicles, which culminated in DA oxidation and α-synuclein...

Alzheimer's disease (AD) presents a critical global challenge, accounting for over 60 % of the 57 million current dementia cases worldwide, with prevalence projected to exceed 100 million by 2050. Traditional diagnostic approaches, such as cerebrospinal fluid (CSF) analysis and neuroimaging are constrained by invasiveness, high costs, and limited accessibility, particularly problematic in aging population where early detection is crucial for effective intervention. This review synthesizes recent...

Our perspective addresses one of the most pressing and timely debates in contemporary neurology and health policy: whether the recent approval of anti-amyloid monoclonal antibodies for Alzheimer's disease should extend to all individuals with mild cognitive impairment (MCI; a large population of tens of millions of individuals worldwide mainly represented in Countries with aged population) who test positive for amyloid biomarkers, despite wide variability in prognosis and therapeutic response...

Dysregulated mitochondrial DNA (mtDNA) promotes inflammatory response and disease progression. However, the mechanism and role of mtDNA-mediated inflammatory activation in the pathogenesis of Parkinson's disease (PD) are not yet clear. This study demonstrates that the injection of mtDNA into the substantia nigra pars compacta induces PD pathology in mice, characterized by the loss of dopaminergic (DA) neurons and the activation of microglia. Transcriptomic profiling of magnetic-activated cell...

Brain derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) play crucial roles in neuronal development, synaptic transmission, and neuroplasticity. Deficits in BDNF/TrkB signalling and trafficking have been identified in several neurodegenerative diseases, including Alzheimer's disease (AD). Individuals with Down syndrome (DS) are at an increased risk of developing AD compared to the general population. Basal forebrain neurons (BFNs) are among the first to...

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The global burden of Parkinson disease (PD) is rapidly shifting towards low-income and middle-income countries (LMICs), which already account for 44% of all individuals with PD. Despite this trend, the populations of LMICs and other under-represented populations defined by ethnicity, sex, geography and minority groups within high-income countries remain largely excluded from PD research. The continuation of these disparities limits our knowledge of disease biology and restricts the applicability...

Detecting senescent cells from single-cell RNA-seq data remains challenging due to the weak and non-specific expression of canonical markers. Here, we demonstrate that simple expansion of these low-signal marker sets does not improve detection accuracy. To address this limitation, we develop ICE (Imputation-based Cell Enrichment), a computational framework that integrates expression imputation with marker refinement. ICE improves the detection of senescent cells in pancreatic β cells and...

CONCLUSIONS: We provide our systematic testing framework as an open-source, publicly available tool that can be utilised to offer novel insights into the genes, tissues and cell types involved in any disease, with the potential for informing drug development and delivery strategies.

Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8^(+) cells, CD4^(+) T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive...

A hallmark of Alzheimer's disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) targeting specific Aβ variants are essential tools for AD research, diagnostics, and therapy. The monoclonal antibodies Aducanumab, Lecanemab, and Donanemab have recently been approved as the first disease-modifying treatments for early AD, highlighting the clinical importance of their exact binding...

Golgi fragmentation is a prominent early hallmark of neurodegenerative diseases such as Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS), yet the shared molecular mechanisms underlying this phenomenon remain poorly understood. Here we identify the E3 ubiquitin ligase ITCH as a central regulator of Golgi integrity and proteostasis. Elevated ITCH disrupts both cis- and trans-Golgi networks, dislocates lysosomal hydrolase sorting factors, and impairs maturation of hydrolases. The...

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive memory loss and cognitive decline. With the global population ageing, the prevalence of AD continues to rise, posing a significant public health challenge. Historically, AD research has centred on two hallmark pathological features: β-amyloid (Aβ) deposition and tau protein hyperphosphorylation. However, repeated failures of therapeutic strategies targeting these pathways in clinical trials have prompted a...

A 'gut-brain axis' is an intricate bidirectional connection between the gut and the central nervous system, serving as a key pathway for signal exchange. However, current in vitro models do not fully capture these dynamic interactions, limiting mechanistic insight and therapeutic testing. Here, we show a 3D human gut-brain-vascular microphysiological platform that integrates lumenized villus-like intestinal barrier, blood vascular-astrocyte interactions, and brain tissue to model...

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