Alzheimer & Parkinson

Alzheimer's disease is triggered by amyloid-β, with symptoms linked to synapse loss. Oligomeric amyloid-β, rather than monomeric or fibrillar amyloid-β, has been proposed to be the proximate mechanistic cause, but the relevant molecular characteristics have remained unclear. To define the biologically relevant species, we isolated a receptor-bound amyloid-β pool from Alzheimer's disease brain by release with a receptor antagonist and purification to homogeneity. This discrete receptor-bound...

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain")....

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This systematic review investigates the mediating factors in the relationship between ambient air pollution exposure and cognitive aging. We identified 16 studies examining 72 unique exposure-mediator-outcome associations for six pollutants (PM2.5, PM10, NO2, NOX, black carbon, and PM1 components). The most studied pollutant was PM2.5 (65% of analyses). Cognitive outcomes included memory, cognitive processing speed, and clinically diagnosed conditions such as dementia incidence. Potential...

Parkinson's disease (PD) motor symptoms are linked to excessive beta band (13-35 Hz) oscillations and basal ganglia-cortical (BGC) synchrony, yet their dynamic inter-relation remains unclear. Based on computational modeling, we hypothesize that transient high-beta (20-35 Hz) BGC coupling induces subcortical low-beta (13-20 Hz) amplification. We recorded intraoperative neural signals from the globus pallidus internus and externus (GPi and GPe, respectively) and motor cortex (M1) in 23 PD patients...

Neuroinflammation is a major secondary driver of Alzheimer's disease (AD). In this issue of Cell Chemical Biology, Carnevale et al.¹ demonstrate that S-nitrosylation of the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway sustains pathological neuroinflammation in AD, identifying a promising therapeutic target for this devastating disease.

Seeded protein misfolding and aggregation are relevant to many neurodegenerative diseases. The archetype are prions: protein-only infectious agents that cause fatal neurodegenerative diseases including Creutzfeldt-Jakob disease (CJD). The recent recognition of iatrogenic amyloid β cerebral amyloid angiopathy (CAA) and Alzheimer's disease, caused by inadvertent seeding of amyloid β pathology following historical medical procedures, raises concerns that these conditions might also be transmitted...

Alzheimer's disease is now defined by underlying pathology, with elevated amyloid-beta (Aβ) sufficient for diagnosis in the absence of cognitive symptoms. We combined longitudinal magnetic resonance imaging and Aβ positron emission tomography data from three cognitively healthy cohorts to examine cortical thickness trajectories in individuals who later converted to Aβ-positive status, using magnetic resonance images acquired years before conversion. Individuals who subsequently developed...

Reference bias is an issue that affects most genomic studies analysing short reads mapped to a reference genome^(1,2). It can be mitigated by mapping to multiple haplotypes represented in a pangenome^(3-5). Here we introduce two new methods to address reference bias: Emblask for pangenome construction and Weaver for mapping to pangenomes at scale. Emblask is a hybrid long- and short-read haplotype-resolved dual assembly pipeline for parent-offspring trio data. Using Emblask, we assembled 698...

Germinal matrix hemorrhage (GMH) is a common complication in premature infants and is associated with a high risk of neurodevelopmental impairment and mortality. Currently, there are no specific neuroprotective treatments available. Exendin-4 is a drug used for the treatment of type 2 diabetes mellitus, and it has shown neuroprotective effects in several neurological disorders including Alzheimer's and Parkinson's disease. In this study, we used the preterm postnatal day 5 rat model of GMH to...

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Alzheimer's disease (AD) remains one of the most challenging neurodegenerative disorders, primarily due to the lack of reliable tools for its early and non-invasive diagnosis. Exosomes, nanosized extracellular vesicles secreted by neural and peripheral cells, have emerged as promising biomarkers reflecting the molecular alterations associated with AD pathogenesis. Fourier Transform Infrared (FTIR) spectroscopy, with its capacity to capture unique biochemical fingerprints of biomolecules,...

Tau protein aggregates adopt distinct conformations across tauopathies, yet the protein interactions engaged by disease-specific polymorphs remain poorly characterized. Here, we demonstrate that conformationally distinct tau polymorphs associate with disease-specific interaction networks across Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Interactome profiling of tau aggregates from PBS- and sarkosyl-soluble brain fractions identified 493...

Synucleinopathies, including idiopathic Parkinson's Disease, are driven by misfolding and aggregation of the 140 residue α-synuclein protein that plays a role in presynaptic vesicle regulation. We describe effects of a modifier, neuronal overexpression of the mouse calcium-activated potassium channel subunit Kcnn1, on a mouse model in which transgenic Thy1.2-driven human A53T α-synuclein directs fully penetrant lethal motor disease. Kcnn1 overexpression increased median survival of these mice...

Alzheimer's disease (AD) is a multifactorial disorder that requires combined therapeutic strategies beyond amyloid clearance. Although GLP-1 receptor agonists show strong mechanistic rationale and supportive epidemiological signals for neuroprotection, large randomized trials in symptomatic AD have yielded negative clinical outcomes and do not support the therapeutic use in AD.

Advanced age is accompanied by progressive metabolic, nutritional, mitochondrial, and neuroimmune dysregulation, which may increase susceptibility to neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting the need to identify modifiable mechanisms that influence disease initiation and progression. Increasing evidence indicates that nutrition, sleep, and circadian rhythms function as an interconnected biological network regulating metabolic...

Alzheimer's Disease (AD), the most prevalent cause of dementia worldwide, is a neurodegenerative disorder that currently has no cure. A growing body of evidence suggests that physical exercise is a potential non-pharmacological strategy in the treatment of AD. Recent findings highlight the involvement of autophagy in the modulatory actions of physical exercise for AD. Here, we present a narrative review of the current knowledge on how exercise impacts AD, specifically focusing on its regulation...

Gut motility dysfunction is a common symptom of Parkinson's disease (PD), but its central mechanisms remain unclear. Here, we utilize multiple mouse models, which mimic both genetic and sporadic PD, to reproduce PD-related gut motility dysfunction. We find that α-synuclein pathology significantly impairs the excitability of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV). Chemogenetic activation of these neurons effectively restores gut motility in PD models, revealing a...

Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the...

We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2...