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1.
Brain Res ; 1841: 149083, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38866308

RESUMO

Alzheimer's disease (AD) affects both grey and white matter (WM), but considerably more is known about the former. Interestingly, WM disruption has been consistently observed and thoroughly described using imaging modalities, particularly MRI which has shown WM functional disconnections between the hippocampus and other brain regions during AD pathogenesis when early neurodegeneration and synapse loss are also evident. Nonetheless, high-resolution structural and functional analyses of WM during AD pathogenesis remain scarce. Given the importance of the myelinated axons in the WM for conveying information across brain regions, such studies will provide valuable information on the cellular drivers and consequences of WM disruption that contribute to the characteristic cognitive decline of AD. Here, we employed a multi-scale approach to investigate hippocampal WM disruption during AD pathogenesis and determine whether hippocampal WM changes accompany the well-documented grey matter losses. Our data indicate that ultrastructural myelin disruption is elevated in the alveus in human AD cases and increases with age in 5xFAD mice. Unreliable action potential propagation and changes to sodium channel expression at the node of Ranvier co-emerged with this deterioration. These findings provide important insight to the neurobiological substrates and functional consequences of decreased WM integrity and are consistent with the notion that hippocampal disconnection contributes to cognitive changes in AD.

2.
Neurobiol Aging ; 106: 207-222, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34303222

RESUMO

The hippocampus is vulnerable to deterioration in Alzheimer's disease (AD). It is, however, a heterogeneous structure, which may contribute to the differential volumetric changes along its septotemporal axis during AD progression. Here, we investigated amyloid plaque deposition along the dorsoventral axis in two strains of transgenic AD (ADTg) mouse models. We also used patch-clamp physiology in these mice to probe for functional consequences of AD pathogenesis in ventral hippocampus, which we found bears significantly higher plaque burden in the aged ADTg group compared to corresponding dorsal regions. Despite dorsoventral differences in amyloid load, ventral CA1 pyramidal neurons of aged ADTg mice exhibited subthreshold physiological changes similar to those previously reported in dorsal neurons, indicative of an HCN channelopathy, but lacked exacerbated suprathreshold accommodation. Additionally, HCN channel function could be rescued by pharmacological manipulation of the endoplasmic reticulum. These observations suggest that an AD-linked HCN channelopathy emerges in both dorsal and ventral CA1 pyramidal neurons, but that the former encounter an additional integrative obstacle in the form of reduced intrinsic excitability.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Placa Amiloide/metabolismo , Células Piramidais/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Progressão da Doença , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Camundongos Transgênicos , Tamanho do Órgão , Técnicas de Patch-Clamp
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