Cdc42GAP deficiency contributes to the Alzheimer’s disease phenotype

Brain, Journal Year: 2023, Volume and Issue: 146(10), P. 4350 - 4365

Published: May 31, 2023

Alzheimer's disease, the most common cause of dementia, is a chronic degenerative disease with typical pathological features extracellular senile plaques and intracellular neurofibrillary tangles significant decrease in density neuronal dendritic spines. Cdc42 member small G protein family that plays an important role regulating synaptic plasticity regulated by Cdc42GAP, which switches from active GTP-bound to inactive GDP-bound states downstream pathways via effector proteins. However, few studies have focused on progression disease. In heterozygous Cdc42GAP mouse model exhibited elevated Cdc42-GTPase activity accompanied increased Cdc42-PAK1-cofilin signalling, we found impairments cognitive behaviours, neuron senescence, loss depolymerization F-actin phenotypes including phosphorylated tau (p-T231, AT8), along soluble insoluble Aβ1-42 Aβ1-40, are consistent mice. Interestingly, these significantly age. Furthermore, results quantitative phosphoproteomic analysis hippocampus 11-month-old GAP mice suggested deficiency induces accelerates disease-like through activation GSK-3β dephosphorylation at Ser9, Ser389 and/or phosphorylation Tyr216. addition, overexpression dominant-negative primary hippocampal cortical neurons reversed hyperphosphorylation. Importantly, signalling pathway, Aβ1-42, Aβ1-40 were sections patients compared those healthy controls. Together, data indicated involved such as deficits, spine loss, AT8) possibly GSK-3β, Thus, provide first evidence phenotypes, may new targets for treatment.

Language: Английский

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Biophysical Modeling of Actin-Mediated Structural Plasticity Reveals Mechanical Adaptation in Dendritic Spines

eNeuro, Journal Year: 2024, Volume and Issue: 11(3), P. ENEURO.0497 - 23.2024

Published: Feb. 21, 2024

Synaptic plasticity is important for learning and memory formation; it describes the strengthening or weakening of connections between synapses. The postsynaptic part excitatory synapses resides in dendritic spines, which are small protrusions on dendrites. One key features synaptic its correlation with size these spines. A long-lasting strength increase [long-term potentiation (LTP)] only possible through reconfiguration actin spine cytoskeleton. Here, we develop an experimentally informed three-dimensional computational model a moving boundary framework to investigate this reconfiguration. Our reactions actin-binding proteins leading cytoskeleton remodeling their effect membrane shape examine enlargement upon LTP. Moreover, find that incorporation perisynaptic elements enhances LTP, exhibiting importance accounting when studying structural shows adaptation repeated stimuli resulting from interactions mechanical forces.

Language: Английский

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Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer’s Disease in Humans

Journal of Alzheimer s Disease, Journal Year: 2022, Volume and Issue: 87(3), P. 1251 - 1290

Published: April 19, 2022

Sporadic Alzheimer's disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in disease, enrichment of ApoE core neuritic plaques, hallmark plaques and tangles, selective vulnerability entorhinal-hippocampal structures.We hypothesized 1) high expression ApoER2 (receptor Reelin) helps explain this anatomical vulnerability; 2) contributes to sAD pathogenesis, by disrupting neuronal delivery Reelin-ApoER2-Dab1 signaling cascades.In vitro biochemical experiments; Single-marker multiplex fluorescence-immunohistochemistry (IHC) postmortem specimens from 26 individuals who died cognitively normal, with mild cognitive impairment or sAD.ApoE peptides proteins were susceptible attack reactive aldehydes, generating lipid-protein adducts crosslinked ApoE-ApoER2 complexes. Using situ hybridization alongside IHC, we that: is strongly expressed terminal zones 'perforant path' projections underlie memory; ApoE, aldehyde-modified Reelin, ApoER2, downstream Reelin-ApoER2 cascade components Dab1 Thr19-phosphorylated PSD95 accumulated vicinity perforant path cases; 3) several ApoE/Reelin-ApoER2-Dab1 pathway markers higher cases positively correlated histological progression deficits.Results demonstrate derangements multiple axis provide proof-of-concept are vulnerable aldehyde-induced adduction crosslinking. Findings foundation implicating receptors sAD.

Language: Английский

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Dendritic spine dynamics in associative memory: A comprehensive review

The FASEB Journal, Journal Year: 2023, Volume and Issue: 37(5)

Published: March 31, 2023

Abstract Associative learning and memory are fundamental behavioral processes through which organisms adapt to complex environments. involves long‐lasting changes in synaptic plasticity. Dendritic spines tiny protrusions from the dendritic shaft of principal neurons, providing structural basis for plasticity brain networks response external stimuli. Mounting evidence indicates that spine dynamics crucial different associative phases, including acquisition, consolidation, reconsolidation. Causally bridging is still limited by suitable tools measure control vivo under behaviorally relevant conditions. Here, we review data remodeling during processing outline open questions.

Language: Английский

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Reducing Cofilin dosage makes embryos resilient to heat stress

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

In addition to regulating the actin cytoskeleton, Cofilin also senses and responds environmental stress. can promote cell survival or death depending on context. Yet, many aspects of Cofilin's role in need clarification. Here, we show that exposing early

Language: Английский

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Resilience mechanisms underlying Alzheimer’s disease

Metabolic Brain Disease, Journal Year: 2025, Volume and Issue: 40(1)

Published: Jan. 6, 2025

Language: Английский

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Synaptic Plasticity in the Hippocampus

Oxford University Press eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 405 - 500

Published: Jan. 1, 2025

Abstract This chapter provides an overview of activity-dependent synaptic plasticity in the hippocampus. It outlines basic properties long-term potentiation (LTP) and depression (LTD) pathways that form core hippocampal trisynaptic circuit, notably Schaffer collateral/commissural (SCC) pathway connecting CA3 to CA1 pyramidal cells. Other significant include projections from medial later entorhinal cortex (EC) distal dendrites principal cells all subfields mossy fiber projection dendate granule The then delves into physiological cell biological mechanisms its contribution hippocampus-dependent memory, including relationship engrams. Another major focus is role dysregulated synaptopathies, with a particular emphasis on neurodevelopmental, psychiatric neurodegenerative brain disorders.

Language: Английский

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Identifying JNK-regulated phosphoproteome markers of anxiety-like behaviour in mouse hippocampus

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Abstract JNKs mediate neuronal damage in neurodegenerative disease and inhibitors of JNK1 have shown anxiolytic anti-depressive effects mice. Here, we analyze the phosphoproteomes hippocampus nucleus accumbens from DJNKI-1 (JNK inhibitor)-infused We correlate phospho-site changes with anxiety-like behaviours elevated plus maze light-dark test identify unique responder Among regulated phosphosites, several lie within GSK3 motifs are exclusively down-regulated. Consistent this, GSK3β is inhibited AKT activated. Importantly, detect multilevel regulation glucose metabolism enzymes including increased PDPK1-S241 phosphorylation, a 5-fold increase pyruvate dehydrogenase (PDHA1)-S-293 signifying its inhibition. This suggests that JNK inhibitor drives metabolic transformation to Warburg response. range identified synaptic cytoskeletal protein phosphosite discussed context JNK-regulated anxiety responses. The annotated hippocampal described here will support mechanistic understanding pathway for future studies brain disorders.

Language: Английский

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Cofilin(s) and Mitochondria: Function Beyond Actin Dynamics

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4094 - 4094

Published: April 25, 2025

ADF/cofilins form a family of small, widely expressed actin-binding proteins, regulating actin dynamics in various cellular and physiological processes all eukaryotes, from yeasts to animals. Changes the expression ADF/cofilin proteins have been demonstrated under pathological conditions. The well-established role cofilin migration, invasion, epithelial-mesenchymal transition, apoptosis, resistance radiotherapy chemotherapy, immune escape, transcriptional dysregulation malignant tumors is primarily attributed its actin-modifying activity. Moreover, drugs targeting this function developed for cancer treatment. However, multilevel regulation, highly diverse effects across conditions, conflicting data on functional consequences altered prompted us explore additional roles cofilin-beyond modulation-particularly involvement lipid metabolism mitochondrial homeostasis. Here, we review recent pathologies, account mutations post-translational modifications these their consequences, dwell K63-type ubiquitination homeostasis, more specifically, process division or mitofission, point out research, describe prospects future studies functions.

Language: Английский

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The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: March 2, 2023

Although the identification of numerous genes involved in neurodevelopmental disorders (NDDs) has reshaped our understanding their etiology, there are still major obstacles way developing therapeutic solutions for intellectual disability (ID) and other NDDs. These include extensive clinical genetic heterogeneity, rarity recurrent pathogenic variants, comorbidity with psychiatric traits. Moreover, a large intragenic mutational landscape is at play some NDDs, leading to broad range symptoms. Such diversity symptoms due different effects DNA variations have on protein functions impacts downstream biological processes. The type functional alterations, such as loss or gain function, interference signaling pathways, yet be correlated most genes. This review aims discussing current how molecular changes group I p21-activated kinases ( PAK1 , 2 3 ), which essential actors brain development function; contribute spectrum Identifying differences PAK structure, regulation spatio-temporal expression may help specific each . Deciphering variation affects these parameters will uncover mechanisms underlying mutation pathogenicity. prerequisite personalized approaches.

Language: Английский

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