Alzheimer & Parkinson
Potentiation of mitochondrial function by mitoDREADD-G<sub>s</sub> reverses pharmacological and neurodegenerative cognitive impairment in mice
Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (G(s)) could rapidly promote the activity of the organelle and possibly...
Advances in PET imaging of protein aggregates associated with neurodegenerative disease
Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins - amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) - are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are...
Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2
Extracellular release and uptake of pathogenic forms of the microtubule-associated protein tau contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease. Defining the cellular mechanisms and pathways for tau entry to human neurons is essential to understanding tauopathy pathogenesis and enabling the rational design of disease-modifying therapeutics. Here, whole-genome, loss-of-function CRISPR screens in human iPSC-derived excitatory neurons, the major...
Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease
Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from...
Overactivation of the inward rectifier K(+) channel 2.1 modulates intrinsic excitability of adult-born granule cells in the male Alzheimer's APP/PS1 mouse model
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction, with spatial memory impairments among the earliest detectable deficits. The dentate gyrus (DG), a critical region for spatial discrimination, exhibits functional alterations in patients with AD. Adult-born granule cells (abGCs) with higher intrinsic excitability are involved in DG-dependent spatial memory. However, it remains unclear the changes in intrinsic excitability of abGCs and...
AI-driven fusion of multimodal data for Alzheimer's disease biomarker assessment
Alzheimer's disease (AD) diagnosis hinges on detecting amyloid beta (Aβ) plaques and neurofibrillary tau (τ) tangles, typically assessed using PET imaging. While accurate, these modalities are expensive and not widely accessible, limiting their utility in routine clinical practice. Here, we present a multimodal computational framework that integrates data from seven distinct cohorts comprising 12, 185 participants to estimate individual PET profiles using more readily available neurological...
Pathogens accelerate features of human aging: A review of molecular mechanisms
(250 words) Many models of aging assume that processes such as cellular senescence or epigenetic alteration occur under sterile conditions. However, humans sustain infection with viral, bacterial, fungal, and parasite pathogens across the course of a lifetime, many of which are capable of long-term persistence in host tissue and nerves. These pathogens-especially members of the human virome like herpesviruses, as well as intracellular bacteria and parasites-express proteins and metabolites...
A unique subpopulation of wild-type neurons recapitulating familial Alzheimer's disease phenotypes
Mutations in the genes encoding APP, Presenilin-1 (PSEN1), and PSEN2 result in early-onset Alzheimer's disease (AD). Previous studies, using iPSC-derived neurons and/or knock-in mice, elucidated the characteristics of neurons expressing familial AD (fAD) mutations. Here, we employ biochemical and state-of-the-art fluorescence imaging assays and report the discovery of a unique subpopulation of wild-type neurons strikingly recapitulating key phenotypes previously identified in the fAD neurons,...
Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy
Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase...
Design of Ig-like binders targeting α-synuclein fibril for mitigating its pathological activities
Parkinson's disease (PD) is characterized by the accumulation and spread of pathological α-synuclein (α-syn) fibrils, which contribute to neuroinflammation and neurodegeneration. Here we show that two immunoglobulin-like (Ig-like) domains derived from α-syn receptors, the D1 domain of lymphocyte-activation gene 3 (L3D1) and the V domain of advanced glycation end-products (vRAGE), effectively block cell surface binding of α-syn fibrils, suppress fibrils-induced neuronal α-syn aggregation, and...
Daily briefing: Lithium supplements reverse Alzheimer's symptoms in mice
No abstract
Supramolecular nanostructure mimics GDNF trophic effects in vitro on human dopaminergic neurons
Peptide-based supramolecular nanostructures offer a versatile platform with substantial promise for clinical translation in regenerative medicine. These systems allow for the incorporation of biologically active sequences and can be engineered to modulate tissue-specific parameters such as stiffness, diffusivity, and biodegradability. We developed here a bioactive supramolecular nanostructure containing a peptide designed based on glial cell-derived neurotrophic factor. These nanostructures form...
Structural analyses define the molecular basis of clusterin chaperone function
Clusterin (apolipoprotein J), a conserved glycoprotein abundant in blood and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein. Dysregulation of clusterin is linked to late-onset Alzheimer disease. Despite its prominent role in extracellular proteostasis, the mechanism of clusterin function remained unclear. Here, we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that...
Plot twist: TET2 clones save the brain
While clonal hematopoiesis (CH) is associated with protection from Alzheimer's disease (AD), a limited understanding of the mechanisms by which this occurs has been a barrier to therapeutic intervention. In a new study, Matatall et al.¹ discover protective mechanisms by which TET2-mutant, but not DNMT3A-mutant, CH impacts dementia pathology and cognition.
Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer's disease
Alzheimer's disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected early. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before...
Erratum for the Research Article "Disruption of BAG3-mediated BACE1 stabilization alleviates neuropathology and memory deficits in a mouse model of Alzheimer's disease" by L. Xia et al
No abstract
Reconstructed cell-type-specific rhythms in human brain link Alzheimer's pathology, circadian stress, and ribosomal disruption
Alzheimer's disease (AD) disrupts behavioral circadian rhythms, but its effects on molecular rhythms in the human brain are poorly understood. Using single-nucleus RNA sequencing (snRNA-seq) from post-mortem cortical samples, we informatically estimated the relative circadian phases of 409 persons with and without AD dementia, reconstructing circadian expression profiles across cell types. Although core clock rhythms were preserved in AD, many cell-type-specific circadian outputs were disrupted....
Strategies to rescue mitochondria in Parkinson's disease: The significance of mitochondrial transfer
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuronal degeneration and pathological α-synuclein accumulation. Mitochondrial dysfunction is a central feature in PD pathogenesis, contributing to impaired bioenergetics, oxidative stress, neuroinflammation, and defective organelle communication. This review synthesizes the current understanding of mitochondrial quality control mechanisms, including fission, fusion, mitophagy, and biogenesis, and their...
Strengthening Africa's brain health and economic resilience
Africa stands at a decisive moment in which urgent action is essential to safeguard its brain health and economic stability. While Africa's population remains predominantly young, it is expanding and aging rapidly. This demographic shift is projected to drive a sharp rise in neurodegenerative diseases, including Alzheimer's, with profound health and economic costs-but brain health research, policy, funding and care across the continent remain critically underdeveloped. In this Perspective, we...
Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA
Amyloid-related imaging abnormalities (ARIA), side effects of anti-amyloid drugs seen in magnetic resonance imaging of the brain, are a major safety concern in patients with Alzheimer's disease. We developed an antibody transport vehicle (ATV) targeting transferrin receptor (TfR) for brain delivery of anti-amyloid-β protein (anti-Aβ) using asymmetrical Fc mutations (ATV^(cisLALA)) that mitigates TfR-related liabilities and retains effector function when bound to Aβ. Administration of...
Alzheimer and Parkinson: Latest results from PubMed
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