Alzheimer & Parkinson

Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson's Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage. Notably, at the intake visit,...

Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, interacts with numerous transcription factors implicated in a wide spectrum of biological responses. It has been identified as a key player in the transcriptional regulation of many mitochondrial components. The activity of PGC1-α is regulated at multiple levels, such as gene expression, transcriptional, post-transcriptional, and post-translational modification. The purpose of this review is to highlight the data...

Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter that has garnered growing attention for its critical roles in cellular signalling and brain function. It regulates NMDA receptors during long-term potentiation, a fundamental mechanism underlying memory consolidation and influences neurotransmission and essential neurophysiological functions. H(2)S is synthesized by three enzymes: cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) and 3-mercaptopyruvate...

Neuroimmunological disorders involve complex interactions between the nervous and immune systems, leading to various severe neurological conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. These disorders are characterized by immune-mediated damage or inflammation within nervous tissue, resulting in cognitive deficits, movement issues, sensory impairments, and other neurological problems. They can affect people of all ages, but incidence increases significantly...

CONCLUSIONS: Artemisinin mediates neuroprotection against Parkinson's disease via regulation of Adcy5-Gch1-BH4 axis in rats. These findings present a beneficial potential for future application of artemisinin on Parkinson's disease treatment.

Tauopathies encompass a large majority of dementia diagnoses and are characterized by toxic neuronal or glial inclusions of the microtubule-associated protein tau. Tau has a high propensity to induce prion-like spreading throughout the brain via a variety of mechanisms, making tauopathy a rapid and lethal form of neurodegeneration that currently lacks an effective therapy or cure. Tau aggregation and neuronal loss associated with this pathology are accompanied by robust neuroinflammation. Innate...

Apolipoprotein E4 (APOE4) is a significant risk for both familial Alzheimer's disease (AD) and sporadic AD with elusive mechanisms. Previous studies mainly focused on the role of APOE4 in familial AD, with less attention to sporadic AD. Our previous study demonstrated that blood cell-derived amyloid-β (Aβ) can enter the brain and induce AD-like pathologies, providing a novel animal model to study sporadic AD to a certain extent. The impacts of APOE4 on Alzheimer-like pathologies and cognitive...

Neuroinflammation drives Alzheimer's disease (AD) pathogenesis. Z-DNA, a non-canonical left-handed DNA structure, activates innate immune signaling through Z-DNA-binding protein 1 (ZBP1). However, the functional significance of ZBP1-mediated Z-DNA detection in AD remains undefined. Here, we found that ZBP1 is amplified in AD microglia, driving innate immune responses and neuroinflammation through sensing Z-form mitochondrial DNA (mtDNA). We show that oxidized mtDNA, generated by amyloid-β...

Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses significant therapeutic challenges due to its complex etiology and limited treatment options. Traditional pharmacotherapies targeting amyloid-β (Aβ) and cholinergic pathways offer modest benefits and are often associated with adverse effects. Emerging evidence implicates gut dysbiosis and the gut-brain axis in the pathogenesis and progression of AD. This review explores the multifactorial pathophysiology of AD and...

Deep brain stimulation (DBS) substantially improves motor symptoms and quality of life in people with movement disorders such as Parkinson disease and dystonia, and it is also being explored as a treatment option for other brain disorders, including treatment-resistant obsessive-compulsive disorder, Alzheimer disease and depression. Two major developments are currently driving progress in DBS research: first, the framework of adaptive DBS, which senses brain activity to infer the momentary state...

Phospho-tau protein p-tau181 is a cerebrospinal fluid biomarker for Alzheimer's disease (AD), while p-tau217 is the most sensitive plasma biomarker for cerebral amyloid β (Aβ) load prior to tau pathology in preclinical AD. Diagnostic and prognostic use of these p-tau biomarkers requires neuropathological interpretation. Here, we analyzed the cellular localization of biomarker p-tau species in postmortem human brains harboring different extents of Aβ plaque and tau pathology. Signals for p-tau217...

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and aggregation of α-Synuclein (α-Syn). While both genetic and environmental factors are implicated in PD pathogenesis, the mechanisms underlying neurodegeneration induced by environmental toxins and associated genetic responses remain largely unknown. Recently, triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to be a critical mediator of toxin-induced motor...

Despite genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci^(1-3), the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent...

Path integration, the ability to track one's position using self-motion cues, is critically dependent on the grid cell network in the entorhinal cortex, a region vulnerable to early Alzheimer's disease pathology. In this study, we examined path integration performance in individuals with subjective cognitive decline (SCD), a group at increased risk for Alzheimer's disease, and healthy controls using an immersive virtual reality task. We developed a Bayesian computational model to decompose path...

Dynamic changes in dopamine, noradrenaline, and serotonin release are believed to causally contribute to the neural computations that support reward-based decision making. Accordingly, changes in signaling by these systems are hypothesized to underwrite multiple cognitive and behavioral symptoms observed in many neurological disorders. Here, we characterize the release of these neurotransmitters measured concurrently in the caudate of patients with Parkinson's disease or essential tremor...

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Understanding how amyloid beta (Aβ) plaques develop and lead to neurotoxicity in Alzheimer's disease remains a major challenge, particularly given the temporal delay and weak correlation between plaque deposition and cognitive decline. This study investigates how the evolving pathology of plaques affects the surrounding tissue, using a knock-in Aβ mouse model (App^(NL-F/NL-F)). We combined mass spectrometry imaging with stable isotope labeling to timestamp Aβ plaques from the moment of their...

The "gut-brain axis" is an emerging target in Alzheimer's disease (AD), although its immunological features remain poorly understood. Using single-cell RNA sequencing, coupled to extensive spectral-tuning flow cytometry validation of the colon immune compartment in the 5XFAD amyloid-β mouse model, we found several AD-associated changes including in B/plasma cell activity. Notably, levels of CXCR4^(+) antibody-secreting cells are reduced in 5XFAD colons. This change corresponds with accumulating...

Alzheimer's disease (AD) is marked by neuroinflammation, neurodegeneration and cognitive decline, with emerging evidence highlighting the critical roles of cytokines and chemokines in its pathogenesis. Regulated cell death is a highly structured and meticulously coordinated series of molecular and signalling processes involving gene expression and protein activity. This mechanism is essential for normal developmental processes and the preservation of tissue homeostasis. Abnormal regulation of...

Age-related hearing loss (ARHL) has emerged as a significant and potentially modifiable risk factor for neurodegenerative disorders, including Alzheimer's disease. A growing body of evidence links ARHL to structural and functional changes in the brain, with implications for cognitive decline and dementia onset. However, both ARHL and dementia are multifactorial conditions shaped not only by biological mechanisms but also by broader social determinants of health. Inequities in access to hearing...