Alzheimer & Parkinson

Alzheimer's disease (AD), the leading cause of senile dementia, lacks effective therapies. While microglia are central to AD pathology, key therapeutic targets remain unclear. Here we identify microglial connexin43 (Cx43) hemichannels as a regulator of microglial reactivity in AD, positioning them as a promising therapeutic target. Post-mortem AD patient tissue showed elevated Cx43 levels in periplaque microglia. In the APP(swe)/PS1(dE9) (APP/PS1) mouse model of amyloidosis, we demonstrated that...

Almost all individuals with Down Syndrome (DS) develop Alzheimer's disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n = 229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD...

Neuronal senescence (i.e., neurescence) is an important hallmark of aging and neurodegeneration, but it remains poorly characterized in the human brain due to the lack of reliable markers. This study aimed to identify neurescence markers based on single-nucleus transcriptome data from postmortem human prefrontal cortex. Using an eigengene approach, we integrated three gene panels: (a) SenMayo, (b) canonical senescence pathway (CSP), and (c) senescence initiating pathway (SIP), to identify...

The identification of Alzheimer's disease (AD)-associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWASs) of AD have successfully identified previously unidentified targets but have almost exclusively used additive genetic models. Here, we performed a family-based GWAS of a recessive inheritance model using whole-genome sequencing from families affected by AD. We found an association between AD risk and the variant rs7161410, which is...

Parkinson's disease is associated with activating mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which suppresses primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum. As a result, there is a decrease in the production of neuroprotective glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN), which normally support the viability of dopaminergic neurons. MLi-2 is a brain-penetrant, selective, and now experimental...

Multimorbidity is common in older adults. However, whether multimorbidity accelerates brain beta-amyloid (Aβ) deposition, the molecular driver of Alzheimer's disease (AD), in humans remains largely unknown. In this study, we selected 435 brain Aβ-positive participants with available longitudinal Aβ-PET data (mean duration 3.9 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Twenty-two self-reported chronic disorders were considered as a measure of the severity of...

Hippocampal degeneration and reduced dopamine levels in Alzheimer's disease are associated with severe memory and cognitive impairments. However, the lack of multifunctional in situ neural chips has posed challenges for integrated investigations of Alzheimer's disease pathophysiology, dopamine dynamics, and neural activity. Therefore, we developed NeuroRevive-FlexChip, a flexible neural interface capable of precise electrical modulation and simultaneous in situ monitoring of dopamine levels and...

Targeting costimulatory signalling pathways, especially inducible T-cell costimulatory (ICOS)-ICOS ligand(ICOSL) co-stimulatory signal, has been widely used as a therapeutic target in autoimmune diseases. Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating and neurodegenerative disease in the central nervous system. At present, few studies are addressing the role of the ICOS-ICOSL co-stimulatory pathway in MS. We aimed to explore the role of anti-ICOS mAb in the immune response...

Preservation of functions in dopaminergic neurons is a potential medication strategy for Parkinson's disease (PD) during perioperative periods. An increasing number of studies have shown that Dexmedetomidine (DEX) plays a neuroprotective role in patients with neurological conditions. However, how DEX exerts its effects on dopaminergic neurons in PD remains unclear. In this research, we report that DEX enhanced the firing activity of dopaminergic neurons via activation of alpha2 (α2)...

Executive dysfunction is a prominent feature of cognitive impairment in Parkinson's disease (PD), affecting approximately 42% of patients. Due to the lack of effective treatment options for the executive dysfunction, it may lead to more severe gait disorder, dementia and be difficult to recuperate. Current studies indicate that music-based intervention (MBI) is an innovative and vital treatment for executive dysfunction. This review aims to describe the ideas-MBI for treating executive...

Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), for which there are currently no successful treatments. Here, we show impaired glycogen metabolism in the brain of a tauopathy Drosophila melanogaster model and people with AD, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen ameliorates the tauopathy phenotypes in...

β-Amyloid (Aβ) is generated from the amyloid precursor protein (APP) through sequential cleavage by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase, where BACE1 acting as the rate-limiting enzyme. Elevated BACE1 levels in the brains of Alzheimer's disease (AD) patients implicate that dysregulated BACE1 expression is crucial to AD pathogenesis. However, the underlying regulatory mechanisms remain unclear. Here, we identified that the G protein subunit β5 gene (Gnb5), a component of the G...

CONCLUSION: HD-tDCS could be a useful complementary treatment for improving sleep and movement in PD-pRBD patients.

Accurate diagnosis and precise estimation of disease progression states are crucial for developing effective treatment plans for patients with parkinsonism. Although various deep learning-based computer-aided diagnostic models have demonstrated benefits, they have been relatively underexplored in parkinsonism owing to limited data and lack of external validation. We introduce the hierarchical wavelet diffusion autoencoder (HWDAE), a generative self-supervised model trained with 1,934 dopamine...

Deep brain stimulation (DBS) has garnered widespread use as an effective treatment for advanced Parkinson's disease. Conventional DBS (cDBS) provides electrical stimulation to the basal ganglia at fixed amplitude and frequency, yet patients' therapeutic needs are often dynamic with residual symptom fluctuations or side effects. Adaptive DBS (aDBS) is an emerging technology that modulates stimulation with respect to real-time clinical, physiological or behavioural states, enabling therapy to...

Mutations in the E3 ubiquitin ligase Parkin gene have been linked to early onset Parkinson's disease. Besides many other roles, Parkin is involved in clearance of damaged mitochondria via mitophagy-a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of...

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Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H^(+)-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive...

Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1...

Nucleocytoplasmic transport defects are observed in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here, we assess mRNA nucleocytoplasmic localization by performing transcriptome-wide profiling on nuclear and cytoplasmic fractions of human iPSC-derived cortical neurons from healthy individuals compared to those with familial AD or FTD. We find that AD- and FTD-causing mutations induce significant changes in mRNA nucleocytoplasmic distribution. We additionally observe the...