Inflammation and Huntington’s disease- a neglected therapeutic target?

Expert Opinion on Investigational Drugs, Год журнала: 2024, Номер 33(5), С. 451 - 467

Опубликована: Май 3, 2024

Huntington's Disease (HD) is a genetic neurodegenerative disease for which there currently no disease-modifying treatment. One of several underlying mechanisms proposed to be involved in HD pathogenesis inflammation; now accumulating evidence that the immune system may play an integral role pathology and progression. As such, modulation could potential therapeutic target HD.

Язык: Английский

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Microglia promote extracellular matrix deposition and restrict excitatory synapse numbers in the mesolimbic dopamine system during healthy aging

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 5, 2024

Abstract Synapse dysfunction is tightly linked to cognitive changes during aging, but underlying mechanisms driving are minimally understood. The extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the status of brain ECM aging remains virtually unexplored. Using novel ECM-optimized proteomic workflows, we discovered striking regional differences in composition aging-induced remodeling. was also aligned with preserved protein abundance across key basal ganglia nuclei. Moreover, using reward-learning paradigms confocal imaging fixed tissue, demonstrated that reduced ECM-synapse remodeling microglial phenotypes, both deficits goal-directed behavior mice. Finally, mouse models microglia ablation premature identified phenotypes promote deposition numbers. Together, these foundational observations implicate glial-ECM interactions regulation function abilities lifespan.

Язык: Английский

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Huntingtin plays an essential role in the adult hippocampus

Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106810 - 106810

Опубликована: Янв. 1, 2025

The consequences of non-pathogenic huntingtin (HTT) reduction in the mature brain are substantial importance as clinical trials for numerous HTT-lowering therapies underway; many which non-selective that they reduce both mutant and wild type protein variants. In this study, we injected CaMKII-promoted AAV-Cre directly into hippocampus adult HTT floxed mice to explore role wild-type (wtHTT) hippocampal pyramidal neurons broader implications its loss. Our findings reveal wtHTT depletion results profound macroscopic morphological abnormalities structure, accompanied by significant reactive gliosis. At synaptic level, identified a marked presynaptic terminals 1-2 months following loss; was contrasted an increased density postsynaptic mushroom spines larger amplitudes spontaneous excitatory currents, indicative disrupted homeostasis. Furthermore, intrinsic neuronal excitability significantly diminished CA1 lacking wtHTT, observed complete loss NMDA receptor-dependent long-term potentiation. Unexpectedly, synapse returned control levels 6-8 loss, despite ongoing presence abnormalities, altered anxiety-related behaviors clear impairments spatial learning memory. Overall, these uncover previously unrecognized critical regulator function brain, highlight potentially vulnerable region adverse effects reduction.

Язык: Английский

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Absence of hippocampal pathology persists in the Q175DN mouse model of Huntington's disease despite elevated HTT aggregation

Journal of Huntington s Disease, Год журнала: 2025, Номер unknown

Опубликована: Фев. 3, 2025

Background Huntington's disease (HD) is a neurodegenerative disorder causing motor, cognitive, and psychiatric impairments, with the striatum being most affected brain region. However, role of other regions, such as hippocampus, in HD remains less understood. Objective Here, we study comparative impact enhanced mHTT aggregation neuropathology hippocampus two mouse models. Methods We utilized zQ175 control model Q175DN mice lacking PGK-Neomycin cassette generated house. performed characterization between by assessing HTT aggregation, neuronal glial pathology, chaperone expression, synaptic density. Results showed that presented both compared to zQ175. Striatal neurons greater susceptibility accumulation Q175DN. On contrary, no signs hippocampal pathology were found absence persisted despite higher levels mHTT. In addition, increased density, decreased Iba1 + microglia density HSF1 specific subregions Conclusions are valuable tool understand fundamental differences toxicity striatal subtypes. Furthermore, our findings also suggest cognitive deficits observed animals might arise from either dysfunction or regions involved processes but not degeneration.

Язык: Английский

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Mitophagy impairment drives microglia activation and results in cognitive deficits in neonatal mice following sevoflurane exposure

Toxicology Letters, Год журнала: 2025, Номер 406, С. 20 - 30

Опубликована: Фев. 14, 2025

Язык: Английский

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