Alzheimer & Parkinson

DLG3, also known as Synapse-associated protein 102 (SAP102), is essential for the organization and plasticity of excitatory synapses within the central nervous system (CNS). It plays a critical role in clustering and moving key components necessary for learning and memory processes. Mutations in the DLG3 gene, which result in truncated SAP102 proteins, have been associated with a range of neurological disorders, including X-linked intellectual disability (XLID), autism spectrum disorders (ASD),...

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The role of microglia in the amyloid cascade of Alzheimer's disease (AD) is debated due to conflicting findings. Using a genetic and a pharmacological approach we demonstrate that depletion of microglia before amyloid-β (Aβ) plaque deposition, leads to a reduction in plaque numbers and neuritic dystrophy, confirming their role in plaque initiation. Transplanting human microglia restores Aβ plaque formation. While microglia depletion reduces insoluble Aβ levels, soluble Aβ concentrations stay...

Plasma membrane protein degradation and recycling are regulated by the endolysosomal system, wherein endocytic vesicles bud from the plasma membrane into the cytoplasm and mature into endosomes and then degradative lysosomes. As such, the endolysosomal system plays a critical role in determining the abundance of proteins on the cell surface and influencing cellular identity and function. Highly polarized cells, like neurons, rely on the endolysosomal system for axonal and dendritic...

Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models in vivo and in vitro. ISG15 overexpression in cells...

Amyloid β (Aβ) forms aggregates in the Alzheimer's disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether Aβ also regulates glial physiology in the normal brain, however, has remained unclear. In this article, we describe the discovery of a novel signaling pathway activated by the monomeric form of Aβ in vitro that plays essential roles in the regulation of microglial activity and the assembly of...

Alzheimer's disease (AD) is the most common type of dementia which affects over than 60 million cases worldwide with higher incidence in low and middle-income countries by 2030. Based on the multifactorial nature of AD different risk factors are linked to the condition considering the brain's β-amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) as its primary hallmarks. Lately, viral photogenes specially after recent SARS-CoV-2 pandemic has gained a lot of attention in promoting the...

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a...

MicroRNAs (miRNAs), referring to a type of non-coding RNAs functioning in various biological processes, participate in the pathophysiology of Alzheimer's disease (AD) through increasing amyloid-beta (Aβ) production, enhancing Tau phosphorylation, and inducing neuroinflammation. Meanwhile, extracellular vesicles (EVs) have been suggested as promising carriers of AD biomarkers as they possess the ability to transmit information from cerebral tissue to peripheral blood. Inspired by the above...

GPR6 is an orphan G protein-coupled receptor with high constitutive activity found in D2-type dopamine receptor-expressing medium spiny neurons of the striatopallidal pathway, which is aberrantly hyperactivated in Parkinson's disease. Here, we solved crystal structures of GPR6 without the addition of a ligand (a pseudo-apo state) and in complex with two inverse agonists, including CVN424, which improved motor symptoms in patients with Parkinson's disease in clinical trials. In addition, we...

Portable, low-field magnetic resonance imaging (LF-MRI) of the brain may facilitate point-of-care assessment of patients with Alzheimer's disease (AD) in settings where conventional MRI cannot. However, image quality is limited by a lower signal-to-noise ratio. Here, we optimize LF-MRI acquisition and develop a freely available machine learning pipeline to quantify brain morphometry and white matter hyperintensities (WMH). We validate the pipeline and apply it to outpatients presenting with mild...

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Microglia, brain innate immune cells, participate in the spread of inflammatory signals and aggregated proteins through secretion of extracellular vesicles (EVs). Selenoprotein P (Sepp1) is a potential regulator of microglial EV secretion. Here, we investigate the effect of Sepp1 silencing on microglial transcriptomics to elucidate the Sepp1 regulatory mechanism of EV secretion and validate this effect in APP^(NL-G-F) knockin mice. Silencing of Sepp1 significantly reduces EV secretion and CD63...

RLIP76 (Rlip), a stress-responsive protein, plays a multifaceted role in cellular function. This protein acts primarily as a glutathione-electrophile conjugate (GS-E) transporter, crucial for detoxifying hazardous compounds and converting them into mercapturic acids. RLIP76 also modulates cytoskeletal motility and membrane plasticity through its role in the Ral-signaling pathway, interacting with RalA and RalB, key small GTPases involved in growth and metastasis. Beyond its ATP-dependent...

Parkinson's disease (PD) is a prevalent neurodegenerative disorder caused by degeneration of dopaminergic neurons, originating from the substantia nigra pars compacta, and characterized by motor symptoms such as bradykinesia, muscle rigidity, resting tremor, and postural instability, as well as non-motor symptoms such as anxiety, depression, reduced sense of smell, cognitive impairment, and visual dysfunction. Emerging evidence highlights the retina as a promising site for non-invasive...

Long-term potentiation (LTP) is a widely studied phenomenon since the underlying molecular mechanisms are widely believed to be critical for learning and memory and their dysregulation has been implicated in many brain disorders affecting cognitive functions. Central to the induction of LTP, in most pathways that have been studied in the mammalian CNS, is the N-methyl-D-aspartate receptor (NMDAR). Philippe Ascher discovered that the NMDAR is subject to a rapid, highly voltage-dependent block by...

Recent studies indicated that the dysregulation of mitochondria-associated endoplasmic reticulum membrane (MAM) could be a significant hub in the pathogenesis of Parkinson's disease (PD). However, little has been known about how MAM altered in PD. This study was aimed to observe morphological changes and analyze proteomic profiles of MAM in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models. In MPTP-treated mice, transmission electron microscopy was applied for MAM...

Alzheimer's disease (AD) is the most common type of dementia and neurodegenerative disease characterized by neurofibrillary tangles (NFTs) and amyloid plaque. Familial AD is caused by mutations in the APP, PSEN1, and PSEN2 genes and these mutations result in the early onset of the disease. Sporadic AD usually affects older adults over the age of 65 years and is, therefore classified as late-onset AD (LOAD). Several risk factors associated with LOAD including the APOE gene have been identified....

Transcranial brain stimulation is a promising technology for safe modulation of brain function without invasive procedures. Recent advances in transcranial optogenetic techniques with external light sources, using upconversion particles and highly sensitive opsins, have shown promise for precise neuromodulation with improved spatial resolution in deeper brain regions. However, these methods have not yet been used to selectively excite or inhibit specific neural populations in multiple brain...

Rare mutations in the gene encoding presenilin2 (PSEN2) are known to cause familial Alzheimer's disease (FAD). Here, we explored how altered PSEN2 expression impacts on the amyloidosis, endolysosomal abnormalities, and synaptic dysfunction observed in female APP knock-in mice. We demonstrate that PSEN2 knockout (KO) as well as the FAD-associated N141IKI mutant accelerate AD-related pathologies in female mice. Both models showed significant deficits in working memory that linked to elevated PSEN2...