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The small HDL particle hypothesis of Alzheimer's disease.

ABSTRACT: We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

SUBMITTER: Martinez AE

PROVIDER: S-EPMC10563117 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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The small HDL particle hypothesis of Alzheimer's disease.

Martinez Ashley E AE Weissberger Gali G Kuklenyik Zsuzsanna Z He Xulei X Meuret Cristiana C Parekh Trusha T Rees Jon C JC Parks Bryan A BA Gardner Michael S MS King Sarah M SM Collier Timothy S TS Harrington Michael G MG Sweeney Melanie D MD Wang Xinhui X Zlokovic Berislav V BV Joe Elizabeth E Nation Daniel A DA Schneider Lon S LS Chui Helena C HC Barr John R JR Han S Duke SD Krauss Ronald M RM Yassine Hussein N HN

Alzheimer's & dementia : the journal of the Alzheimer's Association 20220413 2

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognit ...[more]

PMID: 35416404

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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 small HDL particle hypothesis of Alzheimer's disease.

Publications

The small HDL particle hypothesis of Alzheimer's disease.

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