Dataset Information

The dendritic hypothesis for Alzheimer's disease pathophysiology.

ABSTRACT: Converging evidence indicates that processes occurring in and around neuronal dendrites are central to the pathogenesis of Alzheimer's disease. These data support the concept of a "dendritic hypothesis" of AD, closely related to the existing synaptic hypothesis. Here we detail dendritic neuropathology in the disease and examine how A?, tau, and AD genetic risk factors affect dendritic structure and function. Finally, we consider potential mechanisms by which these key drivers could affect dendritic integrity and disease progression. These dendritic mechanisms serve as a framework for therapeutic target identification and for efforts to develop disease-modifying therapeutics for Alzheimer's disease.

SUBMITTER: Cochran JN

PROVIDER: S-EPMC3989444 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The dendritic hypothesis for Alzheimer's disease pathophysiology.

Cochran J Nicholas JN Hall Alicia M AM Roberson Erik D ED

Brain research bulletin 20131212

Converging evidence indicates that processes occurring in and around neuronal dendrites are central to the pathogenesis of Alzheimer's disease. These data support the concept of a "dendritic hypothesis" of AD, closely related to the existing synaptic hypothesis. Here we detail dendritic neuropathology in the disease and examine how Aβ, tau, and AD genetic risk factors affect dendritic structure and function. Finally, we consider potential mechanisms by which these key drivers could affect dendri ...[more]

PMID: 24333192

Similar Datasets

Project description:Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-? protein (A?), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive A? accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking A? and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by A?-amyloid deposits (A? oligomers and plaques) not only drives A? aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal A? deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal A? amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on ?-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.

Dataset Information

The dendritic hypothesis for Alzheimer's disease pathophysiology.

Publications

The dendritic hypothesis for Alzheimer's disease pathophysiology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets