Alzheimer & Parkinson

Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer's disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across...

The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in...

Brain metabolism perturbation can contribute to traits and diseases. We conducted a genome-wide association study for cerebrospinal fluid (CSF) and brain metabolite levels, identifying 205 independent associations (47.3% new signals, containing 11 new loci) for 139 CSF metabolites, and 32 independent associations (43.8% new signals, containing 4 new loci) for 31 brain metabolites. Of these, 96.9% (CSF) and 71.4% (brain) of the new signals belonged to previously analyzed metabolites in blood or...

Post-mortem investigations indicate that the locus coeruleus (LC) is the initial site of hyperphosphorylated pretangle tau, a precursor to neurofibrillary tangles (NFTs) found in Alzheimer's disease (AD). The presence of pretangle tau and NFTs correlates with AD progression and symptomatology. LC neuron integrity and quantity are linked to cognitive performance, with degeneration strongly associated with AD. Despite their importance, the mechanisms of pretangle tau-induced LC degeneration are...

Proteins work together in nanostructures in many physiological contexts and disease states. We recently developed expansion revealing (ExR), which expands proteins away from each other, in order to support better labeling with antibody tags and nanoscale imaging on conventional microscopes. Here, we report multiplexed expansion revealing (multiExR), which enables high-fidelity antibody visualization of >20 proteins in the same specimen, over serial rounds of staining and imaging. Across all...

Exposure of inner mitochondrial membrane resident protein PHB2 (prohibitin 2) during autophagic removal of depolarized mitochondria (mitophagy) depends on the ubiquitin-proteasome system. This uncovering facilitates the PHB2 interaction with phagophore membrane-associated protein MAP1LC3/LC3. It is unclear whether PHB2 is exposed randomly at mitochondrial rupture sites. Prior knowledge and initial screening indicated that VDAC1 (voltage dependent anion channel 1) might play a role in this...

LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice...

Redox-mediated posttranslational modification, as exemplified by protein S-nitrosylation, modulates protein activity and function in both health and disease. Here, we review recent findings that show how normal aging, infection/inflammation, trauma, environmental toxins, and diseases associated with protein aggregation can each trigger excessive nitrosative stress, resulting in aberrant protein S-nitrosylation and hence dysfunctional protein networks. These redox reactions contribute to the...

Ageing is a major risk factor for various chronic diseases and offers a potential target for developing novel and broadly effective preventatives or therapeutics for age-related conditions, including those affecting the brain. Mechanisms contributing to ageing have been summarized as the hallmarks of ageing, with iron imbalance being one of the major factors. Ferroptosis, an iron-mediated lipid peroxidation-induced programmed cell death, has recently been implicated in neurodegenerative diseases...

Alzheimer's disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by...

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Pathologic α-synuclein (α-syn) aggregates from the gastrointestinal (GI) tract may contribute to Parkinson's disease (PD). Xiang et al.¹ report in Neuron that enteric nervous system-specific expression of asparaginyl endopeptidase (AEP)-truncated α-syn and tau spreads to the brain, synergistically causing PD-related neurodegeneration and neurobehavioral deficits.

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite...

RE-1 silencing transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, its function is lost in Alzheimer's Disease. However, why it becomes inactive remains unclear. Here, we show that the NAD-dependent deacetylase SIRT6 regulates REST expression, location and activity. In the absence of SIRT6, REST is overexpressed but mislocalized, leading to a partial loss of its activity...

Pupil dynamics has emerged as a critical non-invasive indicator of brain state changes. In particular, pupillary-light-responses (PLR) in Alzheimer's disease (AD) patients show potential as biomarkers for brain degeneration. To investigate AD-specific PLR and its underlying neuromodulatory sources, we combine high-resolution awake mouse fMRI with real-time pupillometry to map brain-wide event-related correlation patterns based on illumination-driven pupil constriction ( P c ) and...

A common anatomical core has been described for psychiatric disorders, consisting of the dorsal anterior cingulate cortex (dACC) and anterior insula, processing uncertainty. A common neurophysiological core has been described for other brain related disorders, called thalamocortical dysrhythmia (TCD), consisting of persistent cross-frequency coupling between low and high frequencies. And a common genetic core has been described for yet another set of hypodopaminergic pathologies called reward...

Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the LRRK2 gene affects risk for both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear. We analyzed peritoneal macrophages from R1441C-Lrrk2 knock-in mice and...

Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived...

Parkinson disease (PD) is the fastest growing neurological disorder globally and poses substantial management challenges owing to progressive disability, emergence of levodopa-resistant symptoms, and treatment-related complications. In this Review, we examine the current state of research into PD therapies and outline future priorities for advancing our understanding and treatment of the disease. We identify two main research priorities for the coming years: first, slowing the progression of the...

Almost every recent Alzheimer's disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and nonrandom participation in parental illness surveys, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that the...