Alzheimer & Parkinson

Genome-wide association studies (GWASs) have identified thousands of variants associated with neuropsychiatric disorders (NPDs), including autism spectrum disorder (ASD), schizophrenia (SCZ), and Alzheimer's disease (AD). However, deciphering the "causal" biological mechanisms and pathways through which these variants act remains a major obstacle that hinders translational understanding of NPD pathogenesis. NPDs are highly polygenic with contributions from pleiotropic variants across the allelic...

Parkinson's disease (PD) remains insidious and clinically elusive at early stages due to the lack of precise, non-invasive biomarkers. Given their ability to cross the blood-brain barrier, extracellular vesicles (EVs) offer a promising platform for biomarker discovery in neurodegeneration. Using an affinity-based EV isolation method, we profile EV proteomes and lipidomes from plasma across life stages, followed by targeted validation via parallel reaction monitoring (PRM). We identify both...

Our understanding of how the body communicates with the brain to coordinate their functions is remarkably limited. At the blood-brain barrier (BBB), brain endothelial cells (BECs) are ideally positioned to mediate signaling between blood and brain parenchyma via direct communication with astrocyte perivascular processes (endfeet). We develop a method to define the mouse in vivo astrocyte endfoot proteome, which in combination with BEC-specific RNA-seq, reveal BEC to astrocyte endfoot...

Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer's disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([^(18)F]AZD4694), tau aggregation ([^(18)F]MK-6240) and microglial activation...

In human neuroimaging, brain atlases are essential for segmenting regions of interest (ROIs) and comparing subjects in a common coordinate frame. State-of-the-art atlases derived from histology^(1-3) provide exquisite three-dimensional cytoarchitectural maps but lack probabilistic labels throughout the whole brain: that is, the likelihood of each location belonging to a given ROI. Here we present NextBrain, a probabilistic histological atlas of the whole human brain. We developed artificial...

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)¹. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic². Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to...

The substantia nigra pars reticulata (SNr), a key basal ganglia output nucleus, is modulated by dopamine (DA) believed to be released locally from midbrain DA neurons. Although DA has been proposed to regulate γ-aminobutyric acid (GABA) release from medium spiny neuron (MSN) terminals via presynaptic D1 receptors, the precise mechanisms remain unclear. Using presynaptic optical recordings of synaptic vesicle fusion, calcium influx in D1-MSN synapses together with postsynaptic patch-clamp...

Decades of research on biomarker identification and integration in Alzheimer's disease (AD) have helped to advance biologically driven disease models, disease subtypes, and disease-modifying treatments. Key lessons learned from AD biomarker development include the need for integration of new biological insights, investment in large cross-sectional and longitudinal studies, a multicomponent biomarker approach, and recruitment of clinical trial cohorts and biosamples that are representative of the...

The nucleus basalis of Meynert (nbM), the major cholinergic output of the basal forebrain, regulates cortical modulation, learning, and memory. Dysfunction of the nbM-cortical cholinergic pathway is implicated in neurodegenerative and neurodevelopmental disorders, including Alzheimer's disease (AD) and Down syndrome (DS). Here, we generated human nbM organoids (hnbMOs) from human pluripotent stem cells (hPSCs) containing functional cholinergic projection neurons. Then we reconstructed...

The corpus callosum (CC) is the largest set of white matter fibers connecting the two hemispheres of the brain. In humans, it is essential for coordinating sensorimotor responses and performing associative or executive functions. Identifying which genetic variants underpin CC morphometry can provide molecular insights into the CC's role in mediating cognitive processes. We developed and used an artificial intelligence based tool to extract the midsagittal CC's total and regional area and...

Emerging clinical evidence suggests a link between environmental noise and the severity of Parkinson's disease (PD). However, the effects of high-decibel noise exposure on PD and its underlying mechanisms remain unclear. In this study, we demonstrate that acute noise exposure induces reversible motor deficits in subacute low-dose 6-hydroxydopamine (6-OHDA) mice, a model of presymptomatic early-stage PD, while chronic noise exposure results in irreversible motor deficits and significant loss of...

Alzheimer's disease (AD), the leading cause of dementia, could potentially be mitigated through early detection and interventions. However, it remains challenging to assess subtle cognitive changes in the early AD continuum. Computational modeling is a promising approach to explain a generative process underlying subtle behavioral changes with a number of putative variables. Nonetheless, internal models of the patient remain underexplored in AD. Determining the states of an internal model...

Ageing is a complex biological process driven, in part, by inflammaging. Recent research identifies the ectodysplasin A2 receptor (EDA2R) as a key regulator of inflammaging and a novel biomarker of ageing, with its expression increasing with age across diverse tissues in humans and animal models. Elevated EDA2R gene expression is associated with accelerated ageing, cellular senescence, frailty, obesity, acne, radiation response and increased levels of inflammatory, renal, cardiac and vascular...

Prevention of Alzheimer disease (AD) is a medical challenge owing to its complex pathogenesis, which involves amyloid-β (Aβ) and tau aggregation, neuroinflammation and progressive neurodegeneration. Development of disease-specific biomarkers has transformed our ability to detect AD pathology early, enabling more accurate diagnosis, monitoring and the development of targeted disease-modifying therapies. Consequently, primary and secondary prevention of AD have become feasible goals. In this...

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Physical inactivity is a recognized modifiable risk factor for Alzheimer's disease (AD), yet its relationship with progression of AD pathology in humans remains unclear, limiting the effective translation into prevention trials. Using pedometer-measured step counts in cognitively unimpaired older adults, we demonstrated an association between higher physical activity and slower cognitive and functional decline in individuals with elevated baseline amyloid. Importantly, this beneficial...

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Alzheimer neurodegenerative disease (AD) has had a major impact worldwide, with no effective drugs for treatment. We discovered and reported earlier that neurotrophic factor-α1 (NF-α1)/carboxypeptidase E (CPE) reversed neurodegeneration and cognitive dysfunction in AD mouse models. We then predicted computationally and validated experimentally that CPE interacts with a pharmacophore of six residues on the 5-HT1E receptor (HTR1E) to activate the ERK-BCL2 signaling pathway leading to protection of...

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Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. In AD, there is a gradual impairment of memory and cognitive function that interferes with daily living. The pathophysiology of AD revolves around complex interactions between amyloid-β (Aβ) overproduction and accumulation, followed by tau hyperphosphorylation, which together promote a cascade of neuronal dysfunction and degeneration. AD has two forms, sporadic and familial, with genetic variants such as triggering...