Alzheimer & Parkinson

A rare variant of Apolipoprotein E3 with neuroprotective properties has been identified in autosomal-dominant Alzheimer's disease. In this issue of Neuron, Chen et al.¹ show that direct interaction between this variant and tau blocks tau pathogenesis in rodent models.

Alzheimer's disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ...

The maturation and stabilization of appropriate synaptic connections is a vital step in neural circuit development; however, the molecular signals underlying these processes are not fully understood. We show that astrocytes, through production of glypican 5 (GPC5), are required for maturation and refinement of synapses in the mouse cortex during the critical period. In the absence of astrocyte GPC5, thalamocortical synapses show structural immaturity, including smaller presynaptic terminals,...

Blood phosphorylated (p)-tau 181 and p-tau 217 have been proposed as accurate biomarkers of Alzheimer's disease (AD) pathology. However, blood p-tau 181 is also elevated in amyotrophic lateral sclerosis (ALS) without a clearly identified source. We measured serum p-tau 181 and p-tau 217 in a multicentre cohort of ALS (n = 152), AD (n = 111) cases and disease controls (n = 99) recruited from four different centres. Further, we investigated the existence of both p-tau species using...

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are the most common forms of early-onset dementia. Unlike AD, FTD begins with behavioral changes before the development of cognitive impairment. Dominantly inherited mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of FTD and parkinsonism linked to chromosome 17. These individuals develop abundant filamentous tau inclusions in brain cells in the absence of β-amyloid deposits. Here, we used cryo-electron...

Once taken into consideration, sex differences in neurological diseases emerge in abundance: (i) Stroke severity is significantly higher in females than in males, (ii) Alzheimer's disease (AD) pathology is more pronounced in females, and (iii) conspicuous links with hormonal cycles led to female-specific diagnoses, such as catamenial migraines and epilepsy. While these differences receive increasing attention in isolation, they likely link to similar processes in the brain. Hence, this review...

Menopause is a major biological transition that may influence women's late-life brain health. Earlier estrogen depletion-via earlier menopause-has been associated with increased risk for Alzheimer's disease (AD). Synaptic dysfunction also incites and exacerbates AD progression. We investigated whether age at menopause and synaptic health together influence AD neuropathology and cognitive trajectories using clinical and autopsy data from 268 female decedents in the Rush Memory and Aging Project....

Elucidating the downstream impact of exogenous hormones on the aging brain will have far-reaching consequences for understanding why Alzheimer's disease (AD) predominates in women almost twofold over men. We tested the extent to which menopausal hormone therapy (HT) use is associated with later-life amyloid-β (Aβ) and tau accumulation using PET on N = 146 baseline clinically normal women, aged 51 to 89 years. Women were scanned over a 4.5-year (SD, 2.1; range, 1.3 to 10.4) and 3.5-year (SD, 1.5;...

Fraud undermines Alzheimer's disease research.

Gene regulatory networks (GRNs) provide a global representation of how genetic/genomic information is transferred in living systems and are a key component in understanding genome regulation. Single-cell multiome data provide unprecedented opportunities to reconstruct GRNs at fine-grained resolution. However, the inference of GRNs is hindered by insufficient single omic profiles due to the characteristic high loss rate of single-cell sequencing data. In this study, we developed scMultiomeGRN, a...

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Neuronal cell death is a causative process in traumatic brain injury (TBI)-induced structural and functional impairment of the central nervous system. However, the upstream trigger of TBI-induced neuronal loss and the underlying molecular pathways remain unclear. Zipper-interacting protein kinase (ZIPK) has been shown to be upregulated in Alzheimer's disease and ischemic stroke and to play a role in cellular apoptosis, while its pathological significance in TBI has not been reported. Herein, we...

Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. Mapping the genetics of gene expression in human microglia has identified several loci associated with disease-associated genetic variants in microglia-specific regulatory elements. However, identifying genetic effects on splicing is challenging because of the use of short sequencing reads. Here, we present the isoform-centric microglia genomic atlas...

Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the...

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive decline and distinct neuropathological features. The absence of a definitive cure presents a significant challenge in neurology and neuroscience. Early clinical manifestations, such as memory retrieval deficits and apathy, underscore the need for a deeper understanding of the disease's underlying mechanisms. While amyloid-β plaques and tau neurofibrillary tangles have dominated research...

Oxidative stress is widely recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). While not the sole factor, it is closely linked to critical pathological features, such as the formation of senile plaques and neurofibrillary tangles. The development of agents with antioxidant properties has become an area of growing interest in AD research. Between 2015 and 2024, several antioxidant-targeted drugs for AD progressed to clinical trials, with increasing attention to the...

Alzheimer's disease (AD) is a globally recognized neurodegenerative disorder that severely impairs cognitive function and imposes substantial psychological and financial burdens on patients and their families. The hallmark pathological features of AD include progressive neurodegeneration, extracellular beta-amyloid (Aβ) plaque accumulation, and intracellular hyperphosphorylated tau protein tangles. However, recent studies have identified a subset of patients exhibiting cognitive resilience,...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide. There is no known cure for AD, highlighting an urgent need for new, innovative treatments. Recent studies have shed light on a promising, noninvasive approach using sensory stimulation as a potential therapy for AD. Exposing patients to light and sound pulses at a frequency of 40 hertz induces brain rhythms in the gamma frequency range that are important for healthy brain activity. Using this...

Fraud undermines Alzheimer's disease research.

The Parkinson's disease-linked kinase, PINK1, is a short-lived protein that undergoes cleavage upon mitochondrial import leading to its proteasomal degradation. Under depolarizing conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser^(65). Our experiments reveal that in retinal pigment epithelial cells, only a fraction of PINK1 becomes stabilized after depolarization by electron transport chain inhibitors....