Alzheimer & Parkinson

Impaired sleep is a common aspect of aging and often precedes the onset of Alzheimer's disease. Here, we compare the effects of sleep deprivation in young wild-type mice and their APP/PS1 littermates, a murine model of Alzheimer's disease. After 7 h of sleep deprivation, both genotypes exhibit an increase in EEG slow-wave activity. However, only the wild-type mice demonstrate an increase in the power of infraslow norepinephrine oscillations, which are characteristic of healthy non-rapid eye...

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the...

Dopaminergic (DA) neurons exhibit significant diversity characterized by differences in morphology, anatomical location, axonal projection pattern, and selective vulnerability to disease. More recently, scRNAseq has been used to map DA neuron diversity at the level of gene expression. These studies have revealed a higher than expected molecular diversity in both mouse and human DA neurons. However, whether different molecular expression profiles correlate with specific functions of different DA...

Co-authors say preliminary data on lecanemab fatalities don't support the paper's claims.

Several cardiovascular traits and diseases co-occur with Alzheimer's disease. We mapped their shared genetic architecture using multi-trait genome-wide association studies. Subsequent fine-mapping and colocalisation highlighted 16 genetic loci associated with both Alzheimer's and cardiovascular diseases. We prioritised rs11786896, which colocalised with Alzheimer's disease, atrial fibrillation and expression of PLEC in the heart left ventricle, and rs7529220, which colocalised with Alzheimer's...

The cognitive reserve (CR) hypothesis posits that individuals can differ in how their brain function is disrupted by pathology associated with aging and neurodegeneration. Here, we test this hypothesis in the continuum from cognitively normal to at-risk stages for Alzheimer's Disease (AD) to AD dementia using longitudinal data from 490 participants of the DELCODE multicentric observational study. Brain function is measured using task fMRI of visual memory encoding. Using a multivariate...

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While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In...

Recently approved anti-amyloid immunotherapies for Alzheimer's disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of...

Neurodegenerative diseases, as common diseases in the elderly, tend to become younger due to environmental changes, social development and other factors. They are mainly characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system, and common diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease and so on. Mitochondria are important organelles for adenosine triphosphate (ATP) production in the brain. In recent years, a large...

The therapeutic options for Alzheimer's disease (AD) are limited, underscoring the critical need for finding an effective regulator of Aβ42 production. In this study, with 489 human postmortem brains, we revealed that homotrimer G protein subunit gamma 5 (GNG5) expression is upregulated in the hippocampal-entorhinal region of pathological AD compared with normal controls, and is positively correlated with Aβ pathology. In vivo and in vitro experiments confirm that increased GNG5 significantly...

Immunotherapeutic strategies for Alzheimer's and Parkinson's disease would be facilitated by better measures of inflammation. Here we established an ultra-sensitive single-molecule pull-down immunoassay combined with direct stochastic optical reconstruction microscopy (dSTORM) to measure the number, size and shape of individual extracellular inflammasome ASC specks. We assayed human post-mortem brain, serum and cerebrospinal fluid of patients with Parkinson's and Alzheimer's as well as healthy...

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in...

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...