Alzheimer & Parkinson

Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer's disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced...

The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer's disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1,...

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, remains a diagnostic challenge due to its asymptomatic early stages and the lack of reliable, non-invasive biomarkers. Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-sized membrane-bound particles released by cells into biological fluids and have emerged as promising carriers of disease-specific biomarkers. These vesicles reflect the physiological and pathological state of their parental cells,...

Traumatic brain injury (TBI) is an environmental risk factor for dementia and long-term neurological deficits, posing a significant public health challenge. TBI-induced neuroinflammation involves both brain-resident microglia and peripheral monocyte-derived macrophages (MDMs). Previous research has shown that MDMs contribute to the development of long-term memory deficits, yet their long-term behavior following brain infiltration remains unclear. To address this, our study uses two complementary...

CONCLUSION: Origanum majorana infusion may enhance or regulate antioxidant status and reduce oxidative damage in patients with PD. Further studies are warranted to explore its potential therapeutic benefits.

Parkinson's disease (PD) involves both mitochondrial dysfunction and Lewy body pathology. However molecular links between these features remain unclear. Here, we identify Presenilin-associated rhomboid-like protein (PARL) as a Lewy body component, RARL regulates mitochondrial apoptosis via interacting with orphan nuclear receptor Nur77. Clinical profiling revealed reduced plasma PARL levels in 71 PD patients versus controls (p < 0.001), which correlated with disease severity. In MPP^(+)/MPTP...

The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and...

Pathological aggregation of α-synuclein into amyloid fibrils is a hallmark of synucleinopathies, including Parkinson's disease. Despite this commonality, synucleinopathies display divergent disease phenotypes that have been attributed to disease-specific three-dimensional structures of α-synuclein fibrils, each with unique toxic gain-of-function profiles. The Hsc70 chaperone is remarkable in its ability to disassemble pre-existing amyloid fibrils of different proteins in an ATP and...

Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that...

Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on...

While progressive cognitive decline is the defining feature of Alzheimer's disease (AD), many patients also develop prominent neuropsychiatric symptoms, including anxiety and depression. The circuit-level mechanisms underlying these distinct symptom domains remain poorly understood, and treatments that address both cognitive and noncognitive aspects of AD are limited. Here, we identify anatomically, molecularly, and functionally distinct subpopulations of supramammillary (SuM) neurons that...

Alzheimer's disease (AD) has long resisted effective treatments due to its pathological heterogeneity and cell-type-specific regulatory changes. In this issue of Cell, Li et al. leverage single-cell RNA sequencing and drug repurposing to propose a promising combination therapy, validated through real-world evidence and mouse models, that targets multiple AD-relevant cell types.

Alzheimer's disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug...

Neuroimaging and machine learning are advancing research into the mechanisms of biological aging. In this field, 'brain age gap' has emerged as a promising magnetic resonance imaging-based biomarker that quantifies the deviation between an individual's biological and chronological age of the brain. Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in up to 56,348 individuals unveiled a heritability of...

Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of...

Complex diseases often exhibit sex dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ~17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex dimorphisms during aging with distinct patterns of change in...

Microglial states underlying Alzheimer's disease (AD) have been well characterized in animal models and human samples, yet their regulation remains elusive. In this issue of Neuron, Zhu et al.¹ uncover Adgrg1, which governs a protective microglia phenotype through MYC activation.

Cellular deconvolution estimates cell-type fractions from bulk transcriptomic data, but current methods often overlook cell type-specific expression varying across samples, discrepancies between bulk and single-cell data, or lack guidance on reference data selection and integration. Therefore, we present BLEND, a hierarchical Bayesian method that leverages multiple single-cell reference datasets to perform cellular deconvolution. BLEND estimates cellular fractions accurately by learning the most...

Intercellular nanotubular networks mediate material exchange, but their existence in neurons remains to be explored in detail. We identified long, thin dendritic filopodia forming direct dendrite-dendrite nanotubes (DNTs) in mammalian cortex. Super-resolution microscopy in dissociated neurons revealed DNTs' actin-rich composition and dynamics, enabling long-range calcium ion (Ca^(2+)) propagation. Imaging and machine learning-based analysis validated in situ DNTs as anatomically distinct from...

Integrating single-cell RNA sequencing with Genome-Wide Association Studies (GWAS) can uncover cell types involved in complex traits and disease. However, current methods often lack scalability, interpretability, and robustness. We present seismic, a framework that computes a novel specificity score capturing both expression magnitude and consistency across cell types and introduces influential gene analysis, an approach to identify genes driving each cell type-trait association. Across over...