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Alzheimer & Parkinson

A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis

18 hours 54 minutes ago
Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that...
Shawn C Chafe

Ultradeep N-glycoproteome atlas of mouse reveals spatiotemporal signatures of brain aging and neurodegenerative diseases

18 hours 54 minutes ago
The current depth of site-specific N-glycoproteomics is insufficient to fully characterize glycosylation events in biological samples. Herein, we achieve an ultradeep and precision analysis of the N-glycoproteome of mouse tissues by integrating multiple workflows. The largest N-glycoproteomic dataset to date is established on mice, which contains 91,972 precursor glycopeptides, 62,216 glycoforms, 8939 glycosites and 4563 glycoproteins. The database consists of 6.8 million glyco-spectra...
Pan Fang

Charting γ-secretase substrates by explainable AI

18 hours 54 minutes ago
Proteases recognize substrates by decoding sequence information-an essential cellular process elusive when recognition motifs are absent. Here, we unravel this problem for γ-secretase, an intramembrane-cleaving protease associated with Alzheimer's disease and cancer, by developing Comparative Physicochemical Profiling (CPP), a sequence-based algorithm for identifying interpretable physicochemical features. We show that CPP deciphers a γ-secretase substrate signature with single-residue...
Stephan Breimann

A multicenter longitudinal study of cholinergic subgroups in Parkinson disease

18 hours 54 minutes ago
Parkinson disease (PD) is a heterogeneous syndrome. There is a need for biology-driven subtyping to inform specific therapeutic strategies. In a two-center study with de novo and established PD cohorts, we use vesicular acetylcholine transporter ligand [^(18)F]FEOBV brain PET to assess cholinergic systems changes in early to moderate PD. Principal component analysis (PCA) is applied to data from 245 PD subjects to define cholinergic subgroups at baseline. Three PD subgroups are identified:...
Nicolaas I Bohnen

HDL-bound S1P affects the subventricular niche and early neuropathological features of Alzheimer's disease

18 hours 54 minutes ago
Circulating blood factors are critical for homeostasis of the adult ventricular-subventricular (V-SVZ) and subgranular zones, which contain neural stem cells (NSCs) crucial for sustained neurogenesis. Circulating sphingosine-1-phosphate (S1P) bound to apolipoprotein M (ApoM), a principal component of high-density lipoproteins, is involved in various biological processes, but its role in neurogenic niches is poorly understood. Herein, using Apom^(-/-) mice, we show that blood ApoM-S1P deficiency...
Byung Jo Choi

An O-glycopeptide participates in the formation of distinct Aβ<sub>42</sub> fibril structures and attenuates Aβ<sub>42</sub> neurotoxicity

18 hours 54 minutes ago
The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer's disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine...
Qijia Wei

Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease

18 hours 54 minutes ago
Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte...
Francieli Rohden

Genome-wide association meta-analysis of human olfactory identification discovers sex-specific and sex-differential genetic variants

18 hours 54 minutes ago
Smelling is a human sense, expressing strong sexual dimorphisms. We aim to improve the knowledge of the genetics of human olfactory perception by performing an exploratory genome-wide association meta-analysis of up to 21,495 individuals of European ancestry. By sex-stratified and overall analysis of the identification of twelve odours and an identification score, we discovered ten independent loci, seven of them novel, with trait-wise genome-wide significance (p < 5 × 10^(-8)) involving five...
Franz Förster

DunedinPACNI estimates the longitudinal Pace of Aging from a single brain image to track health and disease

18 hours 54 minutes ago
To understand how aging affects functional decline and increases disease risk, it is necessary to develop measures of how fast a person is aging. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain magnetic resonance imaging, that is, the Dunedin Pace of Aging Calculated from NeuroImaging (DunedinPACNI). Exporting this measure to the Alzheimer's Disease Neuroimaging Initiative, UK Biobank and...
Ethan T Whitman

Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions

18 hours 54 minutes ago
The canonical Alzheimer's Disease (AD) pathological cascade posits that the accumulation of amyloid beta (Aβ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a multi-cohort study (ADNI, A4, HABS-HD) of 1354 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and APOE-ε4 homozygotes are more...
Joseph Giorgio

Boundary complexity of cortical and subcortical areas predicts deep brain stimulation outcomes in Parkinson's disease

18 hours 54 minutes ago
While deep brain stimulation (DBS) remains an effective therapy for Parkinson's disease (PD), sources of variance in patient outcomes are still not fully understood, underscoring a need for better prognostic criteria. Here, we leveraged routinely collected T1-weighted (T1-w) magnetic resonance imaging (MRI) data to derive patient-specific measures of brain structure and evaluate their usefulness in predicting changes in PD medications in response to DBS. Preoperative T1-w MRI data from 231...
Devin Schoen

Enrichment of extracellular vesicles using Mag-Net for the analysis of the plasma proteome

18 hours 54 minutes ago
Extracellular vesicles (EVs) in plasma are composed of exosomes, microvesicles, and apoptotic bodies. We report a plasma EV enrichment strategy using magnetic beads called Mag-Net. Proteomic interrogation of this plasma EV fraction enables the detection of proteins that are beyond the dynamic range of liquid chromatography-mass spectrometry of unfractionated plasma. Mag-Net is robust, reproducible, inexpensive, and requires <100 μL plasma input. Coupled to data-independent mass spectrometry, we...
Christine C Wu

Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis

18 hours 54 minutes ago
Alzheimer's disease (AD), the leading cause of senile dementia, lacks effective therapies. While microglia are central to AD pathology, key therapeutic targets remain unclear. Here we identify microglial connexin43 (Cx43) hemichannels as a regulator of microglial reactivity in AD, positioning them as a promising therapeutic target. Post-mortem AD patient tissue showed elevated Cx43 levels in periplaque microglia. In the APP(swe)/PS1(dE9) (APP/PS1) mouse model of amyloidosis, we demonstrated that...
Yixun Su

Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease

18 hours 54 minutes ago
Almost all individuals with Down Syndrome (DS) develop Alzheimer's disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n = 229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD...
Laia Montoliu-Gaya

Identification of markers for neurescence through transcriptomic profiling of postmortem human brains

18 hours 54 minutes ago
Neuronal senescence (i.e., neurescence) is an important hallmark of aging and neurodegeneration, but it remains poorly characterized in the human brain due to the lack of reliable markers. This study aimed to identify neurescence markers based on single-nucleus transcriptome data from postmortem human prefrontal cortex. Using an eigengene approach, we integrated three gene panels: (a) SenMayo, (b) canonical senescence pathway (CSP), and (c) senescence initiating pathway (SIP), to identify...
Shiva Kazempour Dehkordi

A PKCeta missense mutation enhances Golgi-localized signaling and is associated with recessively inherited familial Alzheimer's disease

1 day 18 hours ago
The identification of Alzheimer's disease (AD)-associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWASs) of AD have successfully identified previously unidentified targets but have almost exclusively used additive genetic models. Here, we performed a family-based GWAS of a recessive inheritance model using whole-genome sequencing from families affected by AD. We found an association between AD risk and the variant rs7161410, which is...
Maria Celeste Gauron

Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson's disease-linked LRRK2-mutant mice

1 day 18 hours ago
Parkinson's disease is associated with activating mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which suppresses primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum. As a result, there is a decrease in the production of neuroprotective glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN), which normally support the viability of dopaminergic neurons. MLi-2 is a brain-penetrant, selective, and now experimental...
Ebsy Jaimon

Association between self-reported multimorbidity and longitudinal brain Abeta deposition in Alzheimer's disease

1 day 18 hours ago
Multimorbidity is common in older adults. However, whether multimorbidity accelerates brain beta-amyloid (Aβ) deposition, the molecular driver of Alzheimer's disease (AD), in humans remains largely unknown. In this study, we selected 435 brain Aβ-positive participants with available longitudinal Aβ-PET data (mean duration 3.9 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Twenty-two self-reported chronic disorders were considered as a measure of the severity of...
Xian-Le Bu

Integrated dopamine sensing and 40 Hz hippocampal stimulation improves cognitive performance in Alzheimer's mouse models

1 day 18 hours ago
Hippocampal degeneration and reduced dopamine levels in Alzheimer's disease are associated with severe memory and cognitive impairments. However, the lack of multifunctional in situ neural chips has posed challenges for integrated investigations of Alzheimer's disease pathophysiology, dopamine dynamics, and neural activity. Therefore, we developed NeuroRevive-FlexChip, a flexible neural interface capable of precise electrical modulation and simultaneous in situ monitoring of dopamine levels and...
Shiya Lv
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Alzheimer and Parkinson: Latest results from PubMed
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