Alzheimer & Parkinson

No abstract

Neurodegenerative disorders such as Alzheimer's and Parkinson's have captured researchers' attention regarding their connection to gut microbiota and dietary factors. Research has shown that changes in our regular dietary consumption can profoundly influence the composition of the gut microbiota, which possesses the capacity to influence brain functioning through a number of mechanisms, suggesting that dietary modifications may serve as promising therapeutic intervention for managing and...

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder globally, is pathologically characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Current therapeutic strategies primarily alleviate clinical symptoms but lack efficacy in halting or reversing neurodegeneration. Recent studies have highlighted the FGF21-ACE2 signaling axis-a synergistic interaction between fibroblast growth factor 21 (FGF21) and angiotensin-converting enzyme 2...

Light has a profound impact on non-visual functions, and clinical evidence suggests bright-light therapy's effectiveness in alleviating motor and non-motor symptoms of Parkinson's disease (PD). However, the neural mechanisms underlying these effects remain unclear. Here, we demonstrate that bright-light treatment alleviates PD symptoms in mice via distinct visual circuits. Specifically, bright-light signals transmitted by the ventral lateral geniculate nucleus alleviate non-motor symptoms, such...

Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer's disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics of the myelin-axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple dysregulated signaling pathways and ligand-receptor interactions,...

The amyloid precursor protein (APP) family is ubiquitously expressed in the mammalian brain and implicated in Alzheimer's disease. APP family proteins participate in synaptic function and their absence impairs cognition. However, how these proteins regulate neural circuits and influence brain-behavior relationships remains unknown. Using in vivo two-photon Ca^(2+)-imaging and Neuropixels, we show that APP family knockout (KO) in excitatory neocortical and hippocampal neurons suppresses neuronal...

Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During...

Exercise's protective effects in Alzheimer's disease (AD) are well recognized, but cell-specific contributions to this phenomenon remain unclear. Here we used single-nucleus RNA sequencing (snRNA-seq) to dissect the response to exercise (free-wheel running) in the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice. Transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons. Exercise...

Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby...

Amyloid aggregates are pathological hallmarks of many human diseases, but how soluble proteins nucleate to form amyloids is poorly understood. Here, we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid-β (Aβ42), the protein that aggregates in Alzheimer's disease. In total, we measure the nucleation rates of >140,000 variants of Aβ42 to accurately quantify the changes in free energy of...

Alzheimer's disease (AD) and hearing loss (HL) are major age-related public health challenges with emerging evidence suggesting their interconnection. This study aimed to investigate global research trends, shared molecular mechanisms, and clinical implications of AD and HL. A total of 349 articles published between 2004 and 2024 were retrieved from the Web of Science Core Collection and analyzed using VOSviewer and CiteSpace. GeneCards and STRING databases were used to explore molecular targets...

Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders, or toxic aggregation and gain-of-function, as in neurodegenerative diseases like Alzheimer's disease or amyotrophic lateral sclerosis. Classical homocystinuria (HCU), an inborn error of sulfur amino acid metabolism, results from cystathionine beta-synthase (CBS) deficiency. CBS...

Neuronal injury is a common complication in patients with diabetes. These injuries include a wide range of neurobehavioral complications that significantly reduce the neuronal network efficiency and quality of life in affected individuals. Currently, diabetes-induced neuronal complications are a major global health challenge, and many studies have been performed to prevent or slow their progression. Semaglutide is a novel form of glucagon-like peptide-1 (GLP-1) agonist agents that has recently...

No abstract

Abnormal aggregation of amyloid-β protein (1-42) (Aβ(42)) is the primary pathology in Alzheimer's disease (AD). Two types of Aβ(42) fibrils have been identified in the insoluble fraction of diseased human brains. Here, we report that the fraction previously deemed 'soluble' during sarkosyl extraction of AD brains actually harbors numerous amyloid fibrils, with a looser bundling than those in the insoluble fraction. Using cryo-electron microscopy (cryo-EM), we discover a third type (type III) of...

During brain development, synapses are initially formed in excess and are later eliminated in an activity-dependent manner. Weak synapses are preferentially removed, but the mechanism linking neuronal activity to synapse removal is unclear. Here, we show that, in the developing mouse visual pathway, inhibiting synaptic transmission induces postsynaptic activation of caspase-3. Caspase-3 deficiency results in defects in synapse elimination driven by both spontaneous and experience-dependent...

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Accurate classification of neurodegenerative disorders remains a challenge in neuroscience. Using open-source electroencephalography (EEG) data, we investigated electrophysiological signatures to differentiate frontotemporal dementia (FTD) from Alzheimer's disease (AD) via complexity measures. Traditional relative band power analysis showed consistent increases in lower-frequency activity but did not distinguish the two disorders after correction. In contrast, fractal dimension and long-range...

Genome-wide association studies have identified many gene polymorphisms associated with an increased risk of developing late-onset Alzheimer's disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing innate immune responses and lipid metabolism of microglia (MG). Here we show that boosting the expression of angiotensin-converting enzyme (ACE), a genome-wide association study LOAD risk-associated gene product, specifically in MG, reduces amyloid-β (Aβ)...

The β-N-methylamino-L-alanine (BMAA) is an emerging neurotoxin associated with human neurodegenerative diseases such as Alzheimer's disease. Here, we report the prevalence of BMAA synthesis in protein forms by marine diatoms and reconstruct its tentative biosynthesis pathway. Remarkably, the BMAA production is strongly induced by iron limitation. Transcriptomic analyses suggest that cysteine synthase (CysK) is involved in BMAA synthesis. This is verified as CRISPR/Cas9-based CysK knockout...