Alzheimer & Parkinson

Traditional approaches to studying astrocyte heterogeneity have mostly focused on analyzing static properties, failing to identify whether subtypes represent intermediate or final states of reactive astrocytes. Here we show that previously proposed neuroprotective and neurotoxic astrocytes are transitional states rather than distinct subtypes, as revealed through time-series multiomic sequencing. Neuroprotective astrocytes are an intermediate state of the transition from a nonreactive to a...

The abnormal deposition of amyloid β (Aβ), produced by proteolytic cleavage events of amyloid precursor protein involving the protease γ-secretase and subsequent polymerization into amyloid plaques, plays a key role in the neuropathology of Alzheimer's disease (AD). Here we show that ErbB3 binding protein 1 (EBP1)/proliferation-associated 2G4 (PA2G4) interacts with presenilin, a catalytic subunit of γ-secretase, inhibiting Aβ production. Mice lacking forebrain Ebp1/Pa2g4 recapitulate the...

Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide...

Infection with herpes simplex virus type 1 (HSV-1) in the brains of APOE4 carriers increases the risk of Alzheimer's disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of APOE4-heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects...

The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that...

Continuous compensation for cerebral dopamine deficiency represents an ideal treatment for Parkinson's disease. Dopamine does not cross the digestive and blood-brain barriers and is rapidly oxidized. The new concept is the intracerebroventricular administration of anaerobic dopamine (A-dopamine) using an abdominal pump connected to a subcutaneous catheter implanted in the third ventricle, near the striatum. An open-label phase 1 study showed no serious adverse reactions induced by A-dopamine in...

The vacuolar-type H^(+)-ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. Its activity and assembly are tightly controlled by multiple pathways, of which phosphorylation-mediated regulation is poorly understood. In this report, we show that in response to starvation stimuli, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2, a subunit of the V(1) domain of the V-ATPase, and phosphorylates ATP6V1B2 at Y68. Y68...

Astragaloside Ⅳ (AS-Ⅳ) improved the motor behavior of Parkinson's disease (PD) mouse but the alteration of imaging in the PD mice brain was unclear. PD models were established by unilateral injection of rotenone (ROT) into the substantia nigra pars compacta (SNc) of mice. AS-Ⅳ (20 mg/kg) was intraperitoneally injected once daily for 14 days. Pole and rotarod tests were performed to evaluate behavioral alterations at 32 weeks. Flow cytometry, electrophysiological recordings techniques, and MRI...

Neurodegenerative disorders (NDDs) have been prevalent for more than a decade, and the number of individuals affected per year has increased exponentially. Among these NDDs, Alzheimer's disease, which causes extreme cognitive impairment, and Parkinson's disease, characterized by impairments in motor activity, are the most prevalent. While few treatments are available for clinical practice, they have minimal effects on reversing the neurodegeneration associated with these debilitating diseases....

The central nervous system (CNS) is endowed with its own resident innate immune cells, the microglia. They constitute approximately 10% of the total cells within the CNS parenchyma and act as 'sentinels', sensing and mitigating any deviation from homeostasis. Nevertheless, under severe acute or chronic neurological injury or disease, microglia are unable to contain the damage, and the reparative activity of monocyte-derived macrophages (MDMs) is required. The failure of the microglia under such...

Cinnamon, renowned for its aromatic flavor, represents one of the most widely used spices worldwide. Cinnamon is also considered beneficial to human health with therapeutic potential for treating various diseases, ranging from diabetes and cancer to neurodegenerative diseases. However, the mechanisms underlying cinnamon's health benefits remain elusive. It is also unclear whether cinnamon has any role in aging. Using C. elegans as a model, here we show that feeding worms cinnamaldehyde (CA), the...

Increased expression of the cyclin-dependent kinase inhibitor p16Ink4a (p16) is detected in neurons of human Alzheimer's disease (AD) brains and during normal aging. Importantly, selective eliminating p16-expressing cells in AD mouse models attenuates tau pathologies and improves cognition. But whether and how p16 contributes to AD pathogenesis remains unclear. To address this question, we tested whether induction of p16 expression in neurons exacerbates AD pathologies. We created a...

Sirtuin-3 (SIRT3) in mitochondria has nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase activity. As such, SIRT3 is crucial in cardiovascular and neurodegenerative diseases. Advanced proteomics and transcriptomics studies have revealed that SIRT3 expression becomes altered when the heart or brain is affected by external stimuli or disease, such as diabetic cardiomyopathy, atherosclerosis, myocardial infarction, Alzheimer's disease, Huntington's disease, and Parkinson's...

Parkinson's disease (PD) is one of the most incapacitating neurodegenerative diseases (NDDs). PD is the second most common NDD worldwide which affects approximately 1-2 percent of people over 65 years. It is an attractive pursuit for artificial intelligence (AI) to contribute to and evolve PD treatments through drug repositioning by repurposing existing drugs, shelved drugs, or even candidates that do not meet the criteria for clinical trials. A search was conducted in three databases Web of...

Local protein synthesis (LPS) in axons is now recognized as a physiological process, participating both in the maintenance of axonal function and diverse plastic phenomena. In the last decades of the 20th century, the existence and function of axonal LPS were topics of significant debate. Very early, axonal LPS was thought not to occur at all and was later accepted to play roles only during development or in response to specific conditions. However, compelling evidence supports its essential and...

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression of the herpesvirus...

We have developed the regionalpcs method, an approach for summarizing gene-level methylation. regionalpcs addresses the challenge of deciphering complex epigenetic mechanisms in diseases like Alzheimer's disease. In contrast to averaging, regionalpcs uses principal components analysis to capture complex methylation patterns across gene regions. Our method demonstrates a 54% improvement in sensitivity over averaging in simulations, providing a robust framework for identifying subtle epigenetic...

Identifying gene expression differences in heterogeneous tissues across conditions is a fundamental biological task, enabled by multi-condition single-cell RNA sequencing (RNA-seq). Current data analysis approaches divide the constituent cells into clusters meant to represent cell types, but such discrete categorization tends to be an unsatisfactory model of the underlying biology. Here, we introduce latent embedding multivariate regression (LEMUR), a model that operates without, or before,...

The protein homeostasis (proteostasis) network encompasses a myriad of mechanisms that maintain the integrity of the proteome by controlling various biological functions, including protein folding and degradation. Alas, ageing-associated decline in the efficiency of this network enables protein aggregation and consequently the development of late-onset neurodegenerative disorders, such as Alzheimer's disease. Accordingly, the maintenance of proteostasis through late stages of life bears the...

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