Alzheimer & Parkinson

P2X purinoreceptor 7 (P2RX7), an ATP-gated ion channel, contributes to Alzheimer's disease (AD) progression, but its molecular mechanisms remain unclear. Here, we show that genetic disruption of P2rx7 mitigates brain atrophy, tau accumulation, and cognitive impairment in PS19 mice. Microglia-specific, but not astrocyte-specific, deletion of P2rx7 suppresses tau propagation. Single-cell RNA sequencing identifies a previously unrecognized first-responding microglial state (FRM) with prominent...

Early sleep disruption is a hallmark of preclinical Alzheimer's disease (AD), but its underlying mechanisms are unclear. The locus coeruleus (LC) dopamine-β-hydroxylase noradrenergic (LC^(DBH)) neurons are vulnerable to early tau pathology in AD. Using P301S transgenic mice and cell-type-specific tau overexpression models, we show that pathological tau accumulation selectively increases the intrinsic excitability of LC^(DBH) neurons. Tau-induced neuronal hyperactivity disrupts sleep homeostasis,...

Hibernation demands rapid brain adaptations, involving cycles of reduced metabolic rate during torpor, followed by brief periods of arousal. Previous studies show hibernation induces a drastic increase in Tau hyperphosphorylation, but a mechanistic connection to disease remains unclear. Using single-nucleus RNA sequencing on hippocampi of golden hamsters, we unveil large transcriptional shifts across the hibernation cycle in all cell types, especially glia. Common transcriptional changes in...

Identifying the neurobiological basis of cognitive vulnerability is essential for preventing Alzheimer's disease (AD). We derived the Alzheimer's Resilience-Vulnerability Connectome (ARC) by contrasting SuperAgers (SA), an extreme phenotype of preserved late-life memory, with AD using resting-state fMRI. ARC distinguished SA from AD in a discovery cohort (N = 290; AUC = 0.85) and replicated independently (N = 143), involving prefrontal, temporal, and insular networks and associating with brain...

Early-onset Alzheimer's disease (EOAD) and late-onset AD (LOAD) differ in clinical presentations and rates of progression. We aimed to compare baseline and longitudinal tau positron emission tomography (PET) burden measured with ^(18)F-flortaucipir and its relationship with clinical variables in amyloid PET-positive, cognitively impaired participants from the Longitudinal Early-Onset Alzheimer's Disease Study (EOAD; n = 390) and Alzheimer's Disease Neuroimaging Initiative (LOAD; n = 211)....

Bone marrow (BM) adiposity changes radically through the lifespan, but this phenomenon is poorly characterized and understood in humans. Large datasets of magnetic resonance imaging (MRI) scans of the head have been collected to study the human brain, but also contain unexploited information about other organs. We developed an artificial neural network that localizes calvarial BM in T1-weighted MRI head scans, enabling us to study its composition in several large MRI datasets, and to model...

Vagus nerve stimulation has shown promising neuroprotective and anti-inflammatory effects in progressive neurodegenerative disorders such as Parkinson's disease. However, its invasive nature introduces procedural and device-related risks. Here we introduce a magnetoelectric particulate system for oral delivery and non-invasive vagus nerve stimulation through the gut. The system comprises a magneto-responsive nickel ferrite core and a piezoelectric barium titanate shell, conjugated with capsaicin...

An age-related neurovascular impairment in nitric oxide (NO)-mediated vasodilation and reciprocal Piezo1-dependent vascular vasoconstriction may precede the accumulation of soluble brain proteins such as amyloid-β (Aβ) and disruption of brain fluid homeostasis in Alzheimer's disease (AD). Preclinical studies suggest that restoring these pathways can enhance neurofluid transport and improve cognitive outcomes. In this study (EudraCT 2021-000625-27), we investigated the effects of sublingual NO...

Organismal physiology depends on continuous, non-hierarchical communication among cells, tissues, and organs. We argue that this communication rests on metabolic flexibility-the capacity of cells and tissues to adapt substrate use to changing energetic demands-and that the hypothalamus serves as the central hub coordinating this flexibility across the body. Using hypothalamic agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons as a model, we show these melanocortin neurons do...

Neuroinflammation and microglial activation are common features in Alzheimer's disease (AD) and excessive alcohol consumption. Alcohol induces liver damage and inflammation, and altered serum aminotransferases have been reported in patients with AD. Small extracellular vesicles (sEVs) and their cargo are emerging as mediators of intercellular communication in AD and alcohol-induced liver injury. However, the effects of alcohol use on AD progression remain to be elucidated. In this study, we...

We developed a machine learning framework grounded in a computational model of brain function and FDG-PET imaging to predict Alzheimer's disease (AD)-type tau across AD and related disorders (ADRD). The model was trained on 1088 research participants spanning normal aging and ADRD with FDG-PET and flortaucipir-PET (FTP-PET). Validation was conducted in: (1) a longitudinal subset of the training cohort (n = 215), (2) Alzheimer's Disease Neuroimaging Initiative (n = 295), and (3) a heretogeneous...

A growing body of evidence implicates the menopausal transition as a neurobiological inflection point in women's brain aging and Alzheimer's disease (AD) vulnerability. Menopause is a midlife neuroendocrine transition characterized by a decline in sex steroid hormones and widespread systemic effects. The brain is not a passive recipient of ovarian hormones but an active endocrine-sensing organ. Menopause, however, does not act in isolation: the ovarian-brain axis is established embryonically,...

Oxidative stress and lipid peroxidation are increasingly recognized as age-related drivers of neurodegeneration, with Parkinson's disease (PD) representing a condition of heightened vulnerability. Among lipid peroxidation products, reactive aldehydes including 4-hydroxy-2-nonenal, malondialdehyde, acrolein, 4-hydroxy-2-hexenal, and crotonaldehyde have emerged not only as biomarkers of oxidative damage, but also as active mediators of neuronal dysfunction. Owing to their electrophilic nature,...

Chaperone-mediated autophagy (CMA), regulated by its lysosomal receptor LAMP2A, is a key pathway for αSynuclein (αSyn) clearance and a direct target of αSyn-related neurotoxicity. Rodent studies show that LAMP2A enhancement reverses neurodegeneration, whereas its deficiency accelerates pathology. To test translational relevance, we examined whether increasing LAMP2A expression in nonhuman primates could mitigate α-synucleinopathy induced by injections of Parkinson's disease patient-derived Lewy...

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The human nigrostriatal pathway, comprising dopaminergic neurons in the ventral midbrain that project to the dorsolateral striatum, is essential for motor control and selectively vulnerable in Parkinson's disease. How this circuit assembles during human development remains poorly understood, and in vitro models capturing its long-range connectivity and spatial organization have been lacking. Here, we establish a compartmentalized, human stem cell-based model of the nigrostriatal pathway by...

CONCLUSIONS: Using a novel graph-based SV calling pipeline, we identify high-quality SVs across a large and ancestrally diverse cohort. Our analyses reveal both common and rare SVs associated with AD. These findings provide valuable insights into the genetic architecture of AD, emphasizing the value of including diverse populations in AD genomic studies.

In this issue of Cell, Brioschi et al. identify cellular musculoaponeurotic fibrosarcoma (cMAF) as a key regulator of brain perivascular macrophages that supports cerebrovascular function through insulin-like growth factor 1 (IGF1) production. This cMAF-IGF1 program is enhanced in Alzheimer's disease (AD), potentially reflecting a protective response that is lost in APOE4 carriers.

Alzheimer's disease (AD) is characterized by marked heterogeneity in the timing and extent of neuronal dysfunction and degeneration. Specific neuronal populations, including entorhinal cortex layer II stellate cells, hippocampal CA1 pyramidal neurons, basal forebrain cholinergic neurons, locus coeruleus noradrenergic neurons, and prefrontal parvalbumin interneurons, show different combinations of functional, pathological, and degenerative vulnerability during disease progression. The strength...

Daniali et al. show that dopamine drives mitochondrial stress, mtDNA release, and cGAS-STING-dependent IL-6 production in human macrophages. These findings suggest a mechanism linking dopaminergic signaling to mtDNA damage signatures increasingly detected in blood from patients with Parkinson's disease.