Alzheimer & Parkinson

Detecting small extracellular vesicles is critical for understanding disease biology and developing diagnostic tools, yet current methods require lengthy isolation steps and lack sensitivity owing to interference from abundant proteins. Here we report on an assay that uses Janus particles that enable rapid, isolation-free detection by exploiting Brownian rotation-induced blinking changes. When vesicles bind, their size significantly alters the blinking frequency, while smaller proteins produce...

Elevated blood levels of phosphorylated tau (p-tau) are diagnostic of Alzheimer disease and are associated with the deposition of amyloid-β in the cerebral neuropil. Elevated p-tau levels have also been associated with cerebral deposition of Danish amyloid and prion protein amyloid. Here we analyzed p-tau in serum from four different cohorts of people with the most common types of systemic amyloidosis, transthyretin (ATTR) amyloidosis and immunoglobulin light chain (AL) amyloidosis. We found...

Microglia are implicated in the progression of Alzheimer's disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can aid in treatment development and monitoring. We analyzed two CSF cohorts (n = 834) that span from unimpaired controls to preclinical and dementia AD stages, identifying 109 dysregulated microglia-related proteins. Enrichment analyses revealed innate immune processes and cellular recruitment in...

Preclinical Alzheimer's disease (AD) is associated with distressing neuropsychiatric symptoms (NPSs) that may accelerate progression toward dementia. Existing approaches probe the symptom-level domain-general or domain-specific neural correlates of NPSs. However, the field lacks process-oriented models of symptom emergence for targeted treatment. We propose one pathway for symptom emergence involving the disruption of emotion regulation (ER) systems by early AD pathology. AD pathology in the...

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, and cholinergic dysfunction. Currently, no disease-modifying drugs are available, and existing symptomatic treatments offer limited efficacy while posing safety concerns, highlighting the urgent need for multi‑target therapeutic strategies. The natural β‑carboline alkaloid harmine has attracted considerable attention due to its favorable...

Extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau are the two main pathological hallmarks of Alzheimer's disease (AD). Although the co-occurrence and synergistic effects of Aβ and Tau are well established, the mechanisms underlying their interplay in a biomolecular condensate environment remain unclear. Here we show that Aβ40 does not undergo liquid-liquid phase separation (LLPS) but significantly enhances Tau phase...

Parkinson's disease (PD) and related familial Parkinsonism are defined by motor dysfunction, but the specific upstream molecular causes of these clinical symptoms can vary widely. We hypothesize that these causes converge onto a limited number of core cellular pathways. To investigate this, we created a collection of 24 genetically well-controlled Drosophila models of familial forms of PD and related mono-genic forms of Parkinsonism. Using unbiased behavioral screening and machine learning we...

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Infraslow (<0.1 Hz) global brain activity, quantified by the global mean blood-oxygenation-level-dependent (gBOLD) signal in resting-state functional magnetic resonance imaging (fMRI), is elevated during sleep and coupled to cerebrospinal fluid (CSF) dynamics, a key pathway for the brain waste clearance implicated in neurodegenerative disorders such as Alzheimer's disease. However, the effect of sleep deprivation on gBOLD activity and its interaction with aging remain poorly understood. Using a...

Neurodegenerative diseases are a set of devastating medical conditions in which neuronal loss associated with the aggregation of toxic proteins leads to progressive cognitive impairment. These diseases are usually modeled in animals by mimicking late disease stages through genetic modifications that aggressively accumulate proteins that damage the brain. However, these diseases typically unfold over decades, and disease-associated genes are known to have important, but understudied, biological...

Identifying biomarkers that precisely track the neurodegenerative component of Alzheimer's disease (AD) is essential for effective clinical management. Here we show that cerebrospinal fluid (CSF) levels of the synaptic proteins NPTX1 and NPTXR are robust indicators of disease severity and future clinical progression. In two independent, multi-ethnic cohorts spanning the AD continuum (n = 635), lower CSF NPTX levels correlate strongly with cognitive impairment and cortical thinning in...

The endoplasmic reticulum (ER) is a central organelle that coordinates protein synthesis and processing, lipid metabolism, Ca²⁺ storage, detoxification, and cellular homeostasis. These processes are rigorously regulated, and when the ER encounters external stimuli, it triggers ER stress, a main mechanism that plays a crucial role in determining cellular fate. In addition to its role in apoptosis, further research has unveiled novel physiological functions of ER stress, encompassing its...

Neurodegenerative diseases are marked by progressive neuronal damage and currently lack a cure. Recently, exercise has emerged as a promising non-pharmacological approach to potentially slow disease progression and enhance cognitive function. This narrative review summarizes the effects of various exercise modalities-including aerobic exercise, resistance training, and balance training-on four major neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, and...

Synaptic dysfunction in Alzheimer's disease (AD) may drive synapse loss and cognitive impairment. Whether AD-related synaptic pathophysiology occurs globally, or in specific synapses, is unclear. We investigate in vivo AD-related synaptic dysfunction during early-stage amyloidosis in App^(NL-G-F) mice. We find reduced presynaptic GABAergic proteins at c-Fos-positive excitatory neurons and increased calcium-mediated activity at excitatory and inhibitory neuronal assemblies. In vivo synaptic...

Lecanemab, an anti-amyloid antibody, has demonstrated a significant clinical benefit in slowing cognitive decline in early Alzheimer's disease (AD). A mechanistic Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model was developed to capture the temporal and biological complexity of AD progression. This QSP model incorporates three interlinked modules reflecting core aspects of AD pathology: Aβ accumulation, tau pathology, and cognitive decline, where Aβ accumulation promotes tau...

Aging is a primary risk factor for chronic diseases, with cellular senescence as an effective target to delay, prevent or alleviate age-related disorders. Here we report in vitro screening outputs from a natural medicinal agent library, wherein dihydromyricetin, a natural flavonoid, showed senotherapeutic potential. Dihydromyricetin protects senescent fibroblasts against further DNA damage and attenuates the senescence-associated secretory phenotype, acting as a senomorphic agent. Proteomics...

Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by...

In Alzheimer's disease, many surviving neurons with tau pathology contain granulovacuolar degeneration bodies (GVBs), neuron-specific lysosomal structures induced by pathological tau assemblies. This could indicate a neuroprotective role for GVBs; however, the mechanism of GVB formation and its functional implications are elusive. Here, we demonstrate that casein kinase 1δ (CK1δ) activity is required for GVB formation. CK1δ is sequestered in the GVB during this process in an autophagy-dependent...

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by progressive amyloid accumulation followed by tau-mediated neurodegeneration. Despite advances in anti-amyloid immunotherapies, important limitations remain, highlighting the need for new therapeutic strategies. Here, we introduce anti-amyloid chimeric antigen receptors expressed in astrocytes (CAR-A) and validate their function in vitro. We show that two CAR-A designs reduce amyloid and associated pathology after...

Genetically altered astrocytes reduce a cardinal pathological feature of Alzheimer's disease.