Alzheimer & Parkinson

Brain aging leads to a decline in cognitive function and a concomitant increase in the susceptibility to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A key question is how changes within individual cells of the brain give rise to age-related dysfunction. Developments in single-cell "omics" technologies, such as single-cell transcriptomics, have facilitated high-dimensional profiling of individual cells. These technologies have led to new and comprehensive...

Neurodegenerative diseases (NDs) are debilitating disorders characterized by the progressive and selective loss of function or structure in the brain and spinal cord. Both chronic and acute forms of these diseases are associated with significant morbidity and mortality, as they involve the degeneration of neurons in various brain regions. Misfolding and aggregation of amyloid proteins into oligomer and β-sheet rich fibrils share as common hallmark and lead to neurotoxicity. Unfortunately,...

Integrating dietary interventions have been extensively studied for their health benefits, such as Alzheimer's disease, Huntington's disease, and aging. However, it is necessary to fully understand the mechanisms of long-term effects and practical applications of these dietary interventions for health. A 10-week intermittent fasting (IMF) regimen was implemented on the aging animals in the current study. The variations of cerebral functions were analyzed employing a comprehensive experimental...

The major pathological feature of Parkinson 's disease (PD), the second most common neurodegenerative disease and most common movement disorder, is the predominant degeneration of dopaminergic neurons in the substantia nigra, a part of the midbrain. Despite decades of research, the molecular mechanisms of the origin of the disease remain unknown. While the disease was initially viewed as a purely neuronal disorder, results from single-cell transcriptomics have suggested that oligodendrocytes may...

Aging increases the risk for Alzheimer's disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in the prefrontal cortex (PFC). We present the first subcellular-resolution spatial transcriptome atlas of the human prefrontal cortex (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages and six age-matched male controls. Our analyses revealed distinct transcriptional alterations across PFC layers,...

Polygenic genome editing in human embryos and germ cells is predicted to become feasible in the next three decades. Several recent books and academic papers have outlined the ethical concerns raised by germline genome editing and the opportunities that it may present^(1-3). To date, no attempts have been made to predict the consequences of altering specific variants associated with polygenic diseases. In this Analysis, we show that polygenic genome editing could theoretically yield extreme...

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...