Alzheimer & Parkinson

Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using singlecell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown that molecularly defined DA subtypes within the substantia nigra (SNc) display distinctive anatomic and functional properties, and differential vulnerability in Parkinson's disease (PD)....

Alzheimer's disease (AD) is the most common neurodegenerative pathology in older persons. The accumulation of amyloid β (Aβ) plaques is a major contributor to AD development. The RNA-binding protein HuD/ELAVL4 has been implicated in the formation of Aβ plaques, but its role in AD is unclear. Here, we report that ablation of HuD from CAMK2A^(+) neurons (HuDcKO) in the 5xFAD mouse model of AD results in a significant reduction of Aβ plaques and the alleviation of some AD-associated behaviors....

Leucine, a branched-chain amino acid (BCAA), exhibits paradoxical effects in Alzheimer's disease (AD), demonstrating both neuroprotective and neurotoxic roles. While prior studies have investigated leucine's systemic and metabolic impacts, its influence on brain structure remains unexplored. This study aimed to fill this critical gap by examining the relationship between serum leucine levels, brain volume metrics, and cognitive performance in individuals across the AD continuum. Serum leucine...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Metabolic dysfunctions, particularly type 2 diabetes mellitus (T2DM), have been implicated in AD pathogenesis, highlighting the potential for novel therapeutic approaches targeting shared underlying mechanisms. Here, we investigate sodium-glucose cotransporter 2 (SGLT2) inhibition as a therapeutic strategy for AD using Enavogliflozin, a potent SGLT2 inhibitor, in the 5XFAD mouse model....

Alzheimer's disease (AD) is initiated by amyloid-beta (Aβ) accumulation in the neocortex; however, the cortical layers and neuronal cell types first susceptible to Aβ remain unknown. Using in vivo two-photon Ca^(2+) imaging in the visual cortex of AD mouse models, we found that cortical layer 5 neurons displayed abnormally prolonged Ca^(2+) transients before substantial plaque formation. Neuropixels recordings revealed that these abnormal transients were associated with reduced spiking and...

The onset of Alzheimer's Disease and Frontotemporal Dementia is closely associated with the aggregation of tau, a multifunctional protein essential for neuronal stability and function. Given the role of tau aggregation in neurodegeneration, understanding the mechanisms behind its fibril formation is crucial for developing therapeutic interventions to halt or reverse disease progression. However, the structural complexity and diverse aggregation pathways of tau present significant challenges,...

Computational research tools have reached a level of maturity that enables efficient simulation of neural activity across diverse scales. Concurrently, experimental neuroscience is experiencing an unprecedented scale of data generation. Despite these advancements, our understanding of the precise mechanistic relationship between neural recordings and key aspects of neural activity remains insufficient, including which specific features of electrophysiological population dynamics (i.e., putative...

The recent emergence of wearable devices will enable large scale remote brain monitoring. This study investigated whether multimodal wearable sleep recordings could help screening for Alzheimer's disease (AD). Measurements were acquired simultaneously from polysomnography and a wearable device, measuring electroencephalography (EEG) and accelerometry (ACM) in 67 elderly without cognitive symptoms and 35 AD patients. Sleep staging was performed using an AI model (SeqSleepNet), followed by feature...

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Parkinson's disease (PD) is thought to develop through a complex interplay of genetic and environmental factors. Epidemiological studies have linked exposure to certain pesticides such as paraquat with elevated PD risk, although how a person's genetic makeup influences disease risk upon exposure remains unknown. Here, we used a genome-wide approach to uncover genes that play a role in resistance to paraquat-induced dopaminergic neurodegeneration in Drosophila. We developed a paraquat exposure...

Loss-of-function mutations in the PINK1 kinase lead to early-onset Parkinson's disease (PD). PINK1 is activated by mitochondrial damage to phosphorylate ubiquitin and Parkin, triggering mitophagy. PINK1 also indirectly phosphorylates Rab GTPases, such as Rab8A. Using an siRNA library targeting human Ser/Thr kinases in HeLa cells, we identified EIF2AK1 [heme-regulated inhibitor (HRI) kinase], a branch of the integrated stress response (ISR), as a negative regulator of PINK1. EIF2AK1 knockdown...

The rapid growth of multi-omics datasets and the wealth of biological knowledge necessitates the development of effective methods for their integration. Such methods are essential for building predictive models and identifying drug targets based on a limited number of samples. We propose a framework called GNNRAI for the supervised integration of multi-omics data with biological priors represented as knowledge graphs. Our framework leverages graph neural networks (GNNs) to model the correlation...

There is strong interest in using the gut microbiome for Parkinson's disease (PD) diagnosis and treatment. However, a consensus on PD-associated microbiome features and a multi-study assessment of their diagnostic value is lacking. Here, we present a machine learning meta-analysis of PD microbiome studies of unprecedented scale (4489 samples). Within most studies, microbiome-based machine learning models accurately classify PD patients (average AUC 71.9%). However, these models are...

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Current Aβ-targeting therapeutics for Alzheimer's disease (AD) only slow cognitive decline due to poor understanding of AD pathogenesis. Here we describe a mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of hippocampal proteins associated with AD pathology. Correspondingly, we developed a brain-penetrant inhibitor of G9a, MS1262, which restored both age-related learning & memory and noncognitive functions in multiple AD mouse models....

The dopamine transporter (DAT) is linked to neuropsychiatric disorders including ADHD, Parkinson's disease, and substance use disorders. Accordingly, DAT is the target of illicit drugs and clinically important medicines. However, the number and function of ligand binding sites in DAT is enigmatic due to conflicting data from available structures and molecular pharmacology. Herein, we design force sensors with DAT ligands and measure their interaction forces with wild-type and mutated DATs, from...

Specialized intramembrane proteases, known as iCLiPs, regulate the processing of transmembrane proteins by releasing intracellular domains, which can function as transcriptional regulators. The signal peptide peptidase-like (SPPL) family of iCLiPs, particularly SPPL2b, has roles in immune regulation, neuronal function, and disease pathogenesis. In the brain, SPPL2b localizes mainly in the plasma membrane of neurons and microglia and is abundant in the cortex and hippocampus. Its known substrates...

The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1-parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinson's disease. However, the molecular basis for specific inhibition of USP30 by small molecules has remained elusive. Here we report the crystal structure of human USP30 in complex with a specific inhibitor,...

Alzheimer's disease (AD) and age-related macular degeneration (AMD) represent the leading causes of dementia and vision impairment in the elderly, respectively. The retina is an extension of the brain, yet these two central nervous system (CNS) compartments are often studied separately. Despite affecting cognition vs. vision, AD and AMD share neuroinflammatory pathways. By comparing these diseases, we can identify converging immune mechanisms and potential cross-applicable therapies. Here, we...