Alzheimer & Parkinson

The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic...

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell...

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Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center...

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau...

Accumulation of the amyloid β (Aβ) peptide, derived from Aβ precursor protein (APP), is a trait of Down syndrome (DS), as is early development of dementia that resembles Alzheimer's disease (AD). Treatments for this AD in DS simply do not. New drug therapies for AD, e.g., Lecanemab, are monoclonal antibodies designed to clear amyloid plaques composed of Aβ. The increasingly real ability to target and dispose of Aβ favors the use of these drugs in individuals with AD in DS, and, perhaps as...

Parkinson's disease (PD) is a progressive neurodegenerative disease with a global burden that affects more often in the elderly. The basal ganglia (BG) is believed to account for movement disorders in PD. More recently, new findings in the original regions in BG involved in motor control, as well as the new circuits or new nucleuses previously not specifically considered were explored. In the present review, we provide up-to-date information related to movement disorders and modulations in PD,...

Gain-of-function mutations in the LRRK2 gene cause Parkinson's disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset of RAB GTPases by LRRK2 is implicated in PD pathogenesis. We find that increased phosphorylation of RAB3A, a cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport of SVPs in iPSC-derived human neurons (iNeurons) expressing hyperactive LRRK2-p.R1441H. Knockout of the opposing protein...

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types' contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including...

Molecular chaperones are protective in neurodegenerative diseases by preventing protein misfolding and aggregation, such as extracellular amyloid plaques and intracellular tau neurofibrillary tangles in Alzheimer's disease (AD). In addition, AD is characterized by an increase in astrocyte reactivity. The chaperone HSPB1 has been proposed as a marker for reactive astrocytes; however, its astrocytic functions in neurodegeneration remain to be elucidated. Here, we identify that HSPB1 is secreted...

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Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex...

Parkinson's disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer's disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The protease domain of HTRA1 is necessary and...

Neuroinflammation is a key feature of Alzheimer's disease (AD). In this work, analysis of single- cell RNA-sequencing (scRNA-seq) data obtained from the brain of patients with AD provides evidence supporting a switch from an innate to an adaptative immune response during tauopathy progression, with both disease-associated microglia (DAM) and CD8+ T cells becoming more frequent at advanced Braak stages.

Amyloidosis of protein caused by fibrillation and aggregation are some of the most exciting new edges not only in protein sciences but also in molecular medicines. The present review discusses recent advancements in the field of neurodegenerative diseases and therapeutic applications with ongoing clinical trials, featuring new areas of protein misfolding resulting in aggregation. The endogenous accretion of protein fibrils having fibrillar morphology symbolizes the beginning of neuro-disorders....

Conjugation of ATG8 to single membranes (CASM) at endolysosomal compartments has attracted attention as the non-autophagic function of the Atg8-family protein conjugation system, and the V-ATPase-ATG16L1 axis has emerged as a core mechanism. Our recent research has revealed that this mechanism contributes to the lysosomal recruitment and activation of LRRK2, a Parkinson disease-associated kinase that phosphorylates a subset of RAB GTPases. The activated LRRK2 under CASM-causing lysosomal stress...

Alzheimer's disease (AD) is the general form of dementia, leading to a progressive neurological disorder characterized by memory loss due to brain cell damage. Artificial Intelligence (AI) assists in the early identification and prediction of AD patients, determining future risks and benefits for radiologists and doctors to save time and cost. Since deep learning (DL) approaches work well with massive datasets and have recently become helpful for AD detection, there remains an area for...

Alzheimer's disease (AD) is caused by the aging process and manifested by cognitive deficits and progressive memory loss. During aging, several conditions, including hypertension, diabetes, and cholesterol, have been identified as potential causes of AD by affecting Sonic hedgehog (Shh) signalling. In addition to being essential for cell differentiation and proliferation, Shh signalling is involved in tissue repair and the prevention of neurodegeneration. Neurogenesis is dependent on Shh...

Age is the primary risk factor for Parkinson's disease (PD), but how aging changes the expression and regulatory landscape of the brain remains unclear. Here we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD postmortem midbrain samples. Combined multiomic analysis along a pseudopathogenesis trajectory reveals that all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We...

Hearing loss is associated with an increased risk of Alzheimer disease (AD). However, the mechanisms of hearing loss promoting the onset of AD are poorly understood. Here we show that hearing loss aggravates cognitive impairment in both wild-type mice and mouse models of AD. Embryonic growth/differentiation factor 1 (GDF1) is downregulated in the hippocampus of deaf mice. Knockdown of GDF1 mimics the detrimental effect of hearing loss on cognition, while overexpression of GDF1 in the hippocampus...