Alzheimer & Parkinson

Alzheimer's disease (AD) is the most common form of dementia with continuum of disease progression of increasing severity from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and lastly to AD. The transition from MCI to AD has been linked to brain hypersynchronization, but the underlying mechanisms leading to this are unknown. Here, we hypothesized that excessive excitation in AD disease progression would shift brain dynamics toward supercriticality across an extended...

Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human...

THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K^(+) channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that...

Dopaminergic subpopulations of the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's disease and are characterized by unique electrophysiological properties. The vulnerable population expresses a T-type calcium channel-mediated afterdepolarization (ADP) and shows rebound activity upon release from inhibition, whereas the resilient population does not have an ADP and is slower to fire after hyperpolarization. This rebound activity can trigger dopamine release in the...

Autoimmunity has been proposed to increase Alzheimer's disease (AD) risk, but evaluating the clinical connection between autoimmune disorders and AD has been difficult in diverse populations. We investigate risk relationships between 26 autoimmune disorders and AD using retrospective observational case-control and cohort study designs based on electronic health records for >300,000 individuals at the University of California, San Francisco (UCSF) and Stanford University. We discover that...

The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals,...

Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced "on-demand" GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect...

Brain age (BA), distinct from chronological age (CA), can be estimated from MRIs to evaluate neuroanatomic aging in cognitively normal (CN) individuals. BA, however, is a cross-sectional measure that summarizes cumulative neuroanatomic aging since birth. Thus, it conveys poorly recent or contemporaneous aging trends, which can be better quantified by the (temporal) pace P of brain aging. Many approaches to map P, however, rely on quantifying DNA methylation in whole-blood cells, which the...

Alzheimer's disease (AD) is an insidious, irreversible, complex neurodegenerative disorder characterized by progressive cognitive decline and memory loss; affecting millions worldwide. Despite decades of research, no effective disease-modifying treatment exists. However, drug repurposing is a progressive step in identifying new therapeutic uses of existing drugs. It has emerged as a promising strategy in the quest to combat AD. Various classes of repurposed drugs, such as antidiabetic,...

Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups...

As the world population ages, new molecular targets in aging and Alzheimer's disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. In this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD. We found that rG4 immunostaining strongly increased in the hippocampus with both age and with AD severity. We further found...

Fraud undermines Alzheimer's disease research.

Myxomatous mitral valve degeneration (MMVD) is one of the most important age-dependent degenerative heart valve disorders in both humans and dogs. It is characterized by the aberrant remodeling of extracellular matrix (ECM), regulated by senescent myofibroblasts (aVICs) transitioning from quiescent valve interstitial cells (qVICs), primarily under TGFB1/TGF-β1 control. In the present study, we found senescent aVICs exhibited impaired macroautophagy/autophagy as evidenced by compromised autophagy...

Astrocytes establish dynamic interactions with surrounding neurons and synchronize neuronal networks within a specific range. However, these reciprocal astrocyte-neuronal interactions are selectively disrupted in epilepsy and Alzheimer's disease (AD), which contributes to the initiation and progression of network hypersynchrony. Deciphering how disrupted astrocyte-neuronal signaling reshapes brain activity is crucial to prevent subclinical epileptiform activity in epilepsy and AD. In this...

Aging is the leading risk factor for Alzheimer's Disease (AD). Understanding the intricate interplay between biological aging and the AD pathophysiology may help to discover innovative treatments. The relationship between aging and core pathways of AD pathogenesis (amyloidopathy and tauopathy) have been extensively studied in preclinical models. However, the potential discordance between preclinical models and human pathology could represent a limitation in the identification of new therapeutic...

Signalling at dopamine D2/D3 receptors is thought to underlie motivated behaviour, pleasure experiences and emotional expression based on animal studies, but it is unclear if this is the case in humans or how this relates to neural processing of reward stimuli. Using a randomised, double-blind, placebo-controlled, crossover neuroimaging study, we show in healthy humans that sustained dopamine D2/D3 receptor antagonism for 7 days results in negative symptoms (impairments in motivated behaviour,...

Tau neurofibrillary tangles (NFTs) in the presence of amyloid-β (Aβ) plaques are required for the diagnosis of Alzheimer's Disease (AD) and closely track with cognitive impairment, yet cognitively normal aged individuals frequently exhibit NFTs arising from tau seed accumulation. This may suggest that not all tau species are equally pathogenic and raises the question of whether unidentified tau modifications augment tau seeding activity and neurodegeneration in AD. We investigated how...

Ageing is associated with cognitive decline, which is a significant factor in the development of dementia. Vitamin B12 (VB12) is crucial for maintaining proper nervous system function, as well as for protein, fat, and carbohydrate metabolism, and DNA synthesis. Moreover, it helps prevent serious health conditions such as pernicious anemia, neurodegenerative diseases, and Alzheimer's disease. VB12 deficiency is common among the elderly population. We found that serum VB12 levels were...

The cGAS-STING pathway mediates innate immune responses to cytosolic DNA. In addition to its well-established role in inducing inflammatory cytokines, activation of the cGAS-STING pathway also induces noncanonical autophagy, a process involving the conjugation of the ATG8 family of ubiquitin-like proteins to membranes of the endolysosomal system. The mechanisms and functions of STING-induced autophagy remain poorly understood. In this study, we demonstrated that STING activation induced...

A microglia subpopulation termed "dark microglia" has been associated with aging and neurodegeneration, although its role has remained elusive. New research from Flury et al. in this issue of Neuron shows that dark microglia drive neurodegeneration via secretion of toxic lipids.¹.