Alzheimer & Parkinson

Compared to individuals carrying two copies of the ε4 allele of apolipoprotein E (APOE), ε2 homozygotes have an approximate 99% reduction in late-onset Alzheimer's disease (AD) risk. Here we develop a knock-in model that allows for an inducible 'switch' between risk and protective alleles (APOE4s2). Gene expression and proteomic analyses confirm that APOE4s2 mice synthesize E4 at baseline and E2 after tamoxifen administration. A whole-body allelic switch results in a metabolic profile resembling...

Alzheimer's disease (AD), a prevalent neurodegenerative disorder, is primarily characterized by β-amyloid (Aβ) deposition. Current therapies alleviate symptoms but lack agents capable of modifying disease progression. Meanwhile, cross-regional studies indicate that AD patients exhibit disrupted gut microbiota composition, which is closely associated with cerebral molecular dysregulation. Building on this gut-brain connection, this study aimed to attenuate AD progression by targeting gut...

Diagnosing Alzheimer's disease (AD) in adults with Down syndrome (DS), a population with a high genetically determined risk of AD, remains challenging. In this large observational study including n = 2329 samples from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) and euploid controls from the Sant Pau Initiative on Neurodegeneration (SPIN) with and without symptomatic AD, we investigate if the strong diagnostic performance of plasma p-tau217 observed in sporadic AD extends to the...

Dopamine (DA) is essential for the production of vigorous actions, but how DA modifies the gain of motor commands remains unclear. Here we show that subsecond DA transients in the striatum of mice are neither required nor sufficient for specifying the vigor of ongoing forelimb movements. Our findings have important implications for our understanding of how DA contributes to motor control under physiological conditions and in Parkinson's disease.

Traumatic brain injury (TBI) increases one's risk of developing Alzheimer's disease and tauopathy. Yet, the mechanisms linking TBI to neurodegenerative disease remain poorly defined. Mounting recent evidence indicates that defects in brain lymphatic drainage contribute to multiple neurodegenerative diseases. Here, we investigated whether promoting brain lymphatic drainage recuperation following TBI via treatment with the lymphangiogenic factor vessel endothelial growth factor C (VEGFC) mitigates...

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The present study compares the predictive performance of serum bile acids with that of conventional Cerebrospinal Fluid (CSF) biomarkers of brain hypometabolism in the Alzheimer's disease (AD) continuum using [^(18)F]-Fluorodeoxyglucose Positron Emission Tomography ([^(18)F]-FDG-PET). Data were extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CSF biomarker data, serum bile acid measurements, and [^(18)F]-FDG-PET data were used. We studied 556 participants, including 185...

Low yields of dopamine neurons in human stem cell-derived neural grafts limit their potential for treating Parkinson's disease. Zhang et al.¹ develop a new three-dimensional differentiation method, informed and refined through careful clonal linage tracing of donor cells post-transplantation, to improve dopamine neuron purity of grafts, eliminating unwanted, off-target populations.

Telomere biology is important for aging and is the cause of the pathogenesis of many neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and brain tumors. Telomere shortening is considered to play a role in neurodegeneration, immune senescence, and cerebrovascular dysfunction. Shorter leukocyte telomere length (LTL) is associated with increased risk and severity of stroke, poorer cognitive outcomes in AD, and increased...

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The diagnosis of Parkinson's disease (PD) is currently based on clinical criteria, centered on the characteristic motor syndrome. However, motor manifestations become evident only after a significant proportion of nigro-striatal dopaminergic neurons have already undergone neurodegeneration. The recent "NSD-ISS" and "SynNeurGe" research frameworks have proposed new biological diagnostic criteria focusing on α-synucleinopathy, neurodegeneration, and genetic biomarkers, independent of clinical...

Fucosylation, a major glycan modification, has been shown to influence neuronal and microglial mechanisms, but whether unconjugated free l-fucose can affect brain function is unknown. l-Fucose can be transported into cells and metabolized by fucokinase (FCSK) via the poorly understood salvage pathway. Using mouse hippocampal slices, we showed that l-fucose enhanced excitatory neurotransmission and long-term potentiation (LTP) through regulation of presynaptic release. Such effects required...

Impaired clearance of amyloid-β (Aβ) contributes to Alzheimer's disease (AD) pathogenesis, but its upstream modulators remain poorly defined. We report secreted Dickkopf (DKK) proteins-DKK1 through DKK4-as previously unrecognized ligands of low-density lipoprotein receptor-related protein 1 (LRP1), a principal Aβ clearance receptor. Analyses of cells derived from a patient with AD, postmortem tissue, and 5×FAD mice reveal that DKK1 and DKK3 are elevated in AD and reduce Aβ uptake and degradation...

Motor symptoms of Parkinson's disease (PD) are associated with dopaminergic neuronal loss. Widespread synaptic reorganization and neural activity changes, including exaggerated beta oscillations and bursting, follow dopamine depletion (DD) of the basal ganglia (BG). Our computational model examines DD-induced neural activity changes and synaptic reorganization in the BG subcircuit comprising the subthalamic nucleus and globus pallidus externus. Calcium-dependent synaptic and structural...

Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer's disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD^(+)) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD^(+) enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD^(+) augmentation...

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...