Alzheimer & Parkinson

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays...

Glycoprotein nonmetastatic melanoma B (GPNMB) is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein in Parkinson's disease (PD). Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB can function in a non-cell-autonomous manner. In the human brain, GPNMB is widely expressed in neurons and microglia. In induced pluripotent stem cell-derived microglia (iMicroglia), GPNMB expression and secretion increase with...

RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to...

CONCLUSIONS: In cognitively unimpaired Asian populations, plasma p-tau217 and Aβ42/40 showed good discriminative performance for Aβ PET positivity. Further standardization, external validation, and prospective evaluation are needed.

Accurate measurement of brain vascular pathology is essential for understanding its role in cognitive aging. Here we classified participants using the amyloid-tau-neurodegeneration framework in a multicenter cohort and identified cerebrospinal fluid brain endothelial-derived small extracellular vesicles (c-BEEVs) as a sensitive biomarker, which correlated with vascular risk factors and the severity of small-vessel disease. c-BEEVs showed high diagnostic performance for vascular cognitive...

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Memory decline, particularly in neurodegenerative disorders such as Alzheimer's disease, represents a critical global public health challenge, with projections exceeding 150 million cases by 2050. Current therapeutic options remain limited: while drugs like donepezil and memantine offer symptomatic relief, and newer agents like lecanemab show modest effects on slowing progression, no disease-modifying cures exist. This underscores the urgent need to refine preclinical models bridging discovery...

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ), with soluble oligomers widely recognized as key drivers of neurotoxicity through disruption of synaptic function, mitochondrial integrity, and cellular homeostasis. Targeting Aβ aggregation therefore represents a compelling therapeutic strategy. Here we report a synthetic peptidomimetic foldamer, M4, as a potent modulator of Aβ42 aggregation. Biophysical analyses demonstrate that M4 binds Aβ with high affinity,...

Parkinson disease (PD), the second most common neurodegenerative disorder, is pathologically linked to dysregulated autophagy, a conserved lysosomal degradation pathway. Current conventional PD therapies are often limited by significant side effects, underscoring the demand for alternative treatment strategies. Drug repurposing of FDA-approved compounds represents a promising approach to address this unmet clinical need. Here, by integrating clinical data analysis, we identified an association...

Alzheimer's disease (AD) is associated with impaired connectivity in critical functional networks. This study investigated the effects of 20 Hz transcranial magnetic stimulation (TMS) on brain network mechanisms in 25 patients with AD, including 17 in the TMS group and 8 in the sham group. We analyzed resting-state functional magnetic resonance imaging data, using the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify neural activity and identify regions of...

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia in older adults. The presence of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) constitutes the two principal neuropathological features of AD. However, current therapies targeting only Aβ or tau remain suboptimal, likely due to intrinsic neuronal and glial dysfunction in affected brain regions. Urolithin A (UroA) is a widely recognized...

Synaptic dysfunction emerges early in Alzheimer's disease, often years before the appearance of clinical symptoms, and is among the most reliable predictors of subsequent cognitive decline. Despite its importance, the cellular events that trigger this early synaptic vulnerability remain poorly defined. Growing evidence points to a critical failure at the interface between neuronal energy metabolism and synaptic signalling, commonly referred to as the mitochondria-synapse axis, suggesting that...

In a recent study in Science, Chen et al. engineer astrocytes with anti-amyloid chimeric antigen receptors (CARs) to enable sustained, antigen-directed clearance of amyloid-β (Aβ) in vivo, revealing how CAR design can shape both pathology and glial responses.

Lipid homeostasis is essential for preserving the structural integrity and functional capacity of the brain. A diverse array of lipids, including cholesterol, phospholipids, and sphingolipids, has been identified as playing pivotal roles. Dysregulation of lipid metabolism is increasingly recognized as a central pathological mechanism in neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Cerebrotendinous...

Genome-wide association studies (GWAS) have identified APOE2 allele as linked to exceptional longevity, with carriers exhibiting a reduced risk of Alzheimer's disease (AD). Apolipoprotein E (APOE), a glycoprotein involved in lipid transport, has three major alleles. However, alterations in lipid metabolism alone do not fully explain APOE2's protective effects. In contrast, APOE4 is the strongest genetic risk factor for AD. To investigate how APOE2 promotes neuronal longevity and confers...

The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of APOE4 remains a critical challenge in the field of AD research. The rare APOE3 Christchurch (APOE3Ch) variant has been suggested to be potentially protective against AD. Our study investigated whether hepatic expression of APOE3Ch could mitigate APOE4-associated AD pathologies. We...

Neurogenesis is the process by which new neurons are generated from neural stem cells (NSCs) and neural progenitor cells (NPCs). Impairment in this process can lead to cognitive and memory deficits, among other issues. Research indicates that defective neurogenesis is closely associated with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). These conditions not only affect a significant global population but also exert profound...

A recent study by Bieri et al. shows that exercise elevates hepatic glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), which cleaves endothelial tissue-nonspecific alkaline phosphatase (TNAP) to rejuvenate cerebrovascular signaling, enhance cognition in aging, and attenuate Alzheimer's-related pathology. This liver-to-brain enzymatic axis positions hepatokines as potent mediators of exercise-induced neuroprotection, which redefines systemic metabolism as a driver of brain...

Blood biomarkers are rapidly becoming established for Alzheimer's Disease (AD) diagnosis. However, there is a need for more scalable tools to reach the 99% of individuals with early cognitive impairment who are not seen in specialist healthcare services. A recent study validated a capillary blood sampling technique to detect the p-tau217 and GFAP biomarkers. Here we used our PROTECT research study to show that these biomarkers, when collected using self-administered fingerprick tests, correlate...

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