Alzheimer & Parkinson

Neurodegenerative diseases (NDs), characterized by progressive neuronal degeneration and manifesting in diverse forms such as memory loss and movement disorders, pose significant challenges due to their complex molecular mechanisms and heterogeneous patient presentations. Diagnosis often relies heavily on clinical assessments and neuroimaging, with definitive confirmation frequently requiring post-mortem autopsy. However, the emergence of Artificial Intelligence (AI) and Machine Learning (ML)...

Microglia and astrocytes are central to the pathogenesis and progression of Alzheimer's Disease (AD), working both independently and collaboratively to regulate key pathological processes such as β-amyloid protein (Aβ) deposition, tau aggregation, neuroinflammation, and synapse loss. These glial cells interact through complex molecular pathways, including IL-3/IL-3Ra and C3/C3aR, which influence disease progression and cognitive decline. Emerging research suggests that modulating these pathways...

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. It is characterized by the accumulation of beta-amyloid and phosphorylated tau, synaptic damage, and mitochondrial abnormalities in the brain, leading to the progressive loss of cognitive function and memory. In AD, emerging research suggests that lifestyle factors such as a healthy diet and regular exercise may play a significant role in delaying the onset and progression of the...

Previous studies have indicated increased dementia risk associated with fine particulate matter (PM(2.5)) exposure; however, the findings are inconsistent. In this systematic review, we assessed the association between long-term PM(2.5) exposure and dementia outcomes using the Burden of Proof meta-analytic framework, which relaxes log-linear assumptions to better characterize relative risk functions and quantify unexplained between-study heterogeneity (PROSPERO, ID CRD42023421869). Here we...

Accurate staging of Alzheimer's disease (AD) pathology is crucial for therapeutic trials and prognosis, but existing fluid biomarkers lack specificity, especially for assessing tau deposition severity, in amyloid-beta (Aβ)-positive patients. We analyze cerebrospinal fluid (CSF) samples from 136 participants in the Alzheimer's Disease Neuroimaging Initiative using more than 6,000 proteins. We apply machine learning to predict AD pathological stages defined by amyloid and tau positron emission...

CONCLUSIONS: This study highlights common neural targets in MCI, AD, and bvFTD and their link with cognitive impairment, emphasizing the value of LSM within a transdiagnostic approach to neurodegenerative diseases.

Why there is sex-biased susceptibility to cerebrovascular dysfunction remains enigmatic. Vandal et al.¹ reveal a sex-specific vulnerability to endothelial deficiency in CD2AP, an Alzheimer's disease risk gene, with impaired cerebrovascular reactivity, compromised cerebrovascular function, and cognitive decline, highlighting sex as an important biological variable in Alzheimer's disease.

The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer's disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared with the common APOE3 allele. Using single-nucleus RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, we found that AD-associated transcriptomic changes were highly APOE genotype dependent. Comparing AD with controls, APOE2 carriers showed upregulated synaptic and...

Several studies have shown that Parkinson's disease causative gene products, including α-synuclein (α-syn), display tight links with the tumor suppressor p53. The purpose of this study is to determine the implication of α-syn in glioblastoma development and elucidate how it elicits a tumor suppressor function. We show that the expression of α-syn, a TP53 transcriptional target and a key molecular player in Parkinson's disease, is detected in 1p/19q-codeleted and isocitrate dehydrogenase...

Transcranial ultrasound stimulation (TUS) offers precise, non-invasive neuromodulation, though its impact on human deep brain structures remains underexplored. Here we examined TUS-induced changes in the basal ganglia of 10 individuals with movement disorders (Parkinson's disease and dystonia) and 15 healthy participants. Local field potentials were recorded using deep brain stimulation (DBS) leads in the globus pallidus internus (GPi). Compared to sham, theta burst TUS (tbTUS) increased theta...

Alzheimer's disease (AD) is a progressively worsening neurodegenerative disorder characterized primarily by the deposition of amyloid beta (Aβ) plaques in the brain and the abnormal aggregation of tau protein forming neurofibrillary tangles. These pathological changes lead to impaired neuronal function and cell death, subsequently affecting the structure and function of the brain. Fibroblast growth factors (FGFs) are a group of proteins that play crucial roles in various biological processes,...

Female Alzheimer's disease (AD) patients display greater cognitive deficits and worse AD pathology as compared to male AD patients. In this study, we found that conditional knockout (cKO) of Atg5 in female microglia failed to obtain disease-associated microglia (DAM) gene signatures in familiar AD mouse model (5xFAD). Next, we analyzed the maintenance and neurogenesis of neural stem cells (NSCs) in the hippocampus and subventricular zone (SVZ) from 5xFAD mice with Atg5 cKO. Our data indicated...

Changes in β-amyloid (Aβ) and hyperphosphorylated tau (T) in brain and cerebrospinal fluid (CSF) precede Alzheimer's disease (AD) symptoms, making the CSF proteome a potential avenue to understand disease pathophysiology and facilitate reliable diagnostics and therapies. Using the AT framework and a three-stage study design (discovery, replication, and meta-analysis), we identified 2,173 analytes (2,029 unique proteins) dysregulated in AD. Of these, 865 (43%) were previously reported, and 1,164...

The Enteric Nervous System (ENS), often called the "second brain," is a complex network of neurons and glial cells within the gastrointestinal (GI) tract. It functions autonomously while maintaining close communication with the central nervous system (CNS) via the gut-brain axis (GBA). ENS dysfunction plays a crucial role in neurodegenerative and neurodevelopmental disorders, including Parkinson's disease, Alzheimer's disease, and autism spectrum disorder. Disruptions such as altered...

Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary...

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Small molecules that can reduce the neurotoxic beta-amyloid (Aβ) aggregates in the brain provide a potential treatment for Alzheimer disease (AD). Most screening methods for small-molecule hits focus on the overall Aβ aggregations without a specific target, such as the very first association step (i.e., nucleation) en route to the Aβ oligomers. Located in the middle of a full-length Aβ peptide, Aβ(19-20) (diphenylalanine or FF) nucleates the neurotoxic Aβ oligomer formation. Here, we innovate a...

Alzheimer's disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here, we used extensive molecular dynamics (MD) simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental...

In primary age-related tauopathy (PART) and Alzheimer's disease (AD), tau aggregates share a similar structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, transcriptional similarities between PART and AD and gene expression changes within tau-pathology-bearing neurons are largely unknown. Using GeoMx spatial transcriptomics, mRNA was quantified in hippocampal neurons with and without tau pathology in PART and AD. Synaptic genes were down-regulated...