A single enzyme in a lesser-known brain structure—the choroid plexus—may be gumming up the brain’s waste-disposal system for the amyloid-β protein that drives Alzheimer’s disease. Alzheimer’s affects roughly 850,000 people in the UK, and no cure exists. The brain continuously produces amyloid-β, clearing about 8% of it every hour. That clearance relies heavily on the choroid plexus, a thin sheet of cells that makes cerebrospinal fluid and shunts waste out of the brain. As people age, these cells fill with lipid droplets, and amyloid-β accumulates there. The enzyme SOAT1 converts excess cholesterol into storage droplets, and the researchers suspect it is the root cause of this clogging. This project uses genetically modified mice to test whether shutting down SOAT1 specifically in the choroid plexus can restore amyloid-β clearance and reverse Alzheimer’s-like pathology. If it works, the approach could lead to a gene therapy that targets the choroid plexus directly, avoiding the toxicity that doomed earlier SOAT1-inhibitor drugs for atherosclerosis. The work is fundamental—it first needs to prove the enzyme’s role in this specific tissue—but it could open a new route for treating Alzheimer’s by fixing the brain’s own plumbing.
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Alzheimer’s disease (AD), an age-related neurodegenerative disease, afflicts an estimated 850,000 individuals in the UK. AD develops over time and the progressive damage to brain cells manifests in the later stages as severe memory loss and the inability to perform daily tasks, ultimately resulting in death. Currently, there is no cure for AD. Amyloid plaques and neurofibrillary tangles in the brain are hallmarks of AD. Accumulation of amyloid-ß (Aß) peptides is commonly considered the trigger of developing AD. Aß is continuingly produced, with an average turnover rate of approximately 8% per hour in the healthy adult human brain. Thus, Aß clearance is crucial for maintaining its homeostasis and preventing its aggregation and pathological consequences. Aß is mainly removed from the brain by the flow of brain fluid, including the interstitial fluid and cerebrospinal fluid (CSF), via the blood-brain barrier, blood-CSF barrier (BCSFB), and CSF/perivascular pathways. CSF is primarily secreted from the choroid plexus (CP), a lesser known but important brain structure suspended in the CSF-filled ventricles. The CP is comprised of a layer of epithelial cells (CPe) jointed by tight junctions surrounding a highly vascularized stroma with fenestrated capillaries, thus forming the BCSFB and connecting the peripheral circulation with CSF/brain. The CP is a key component of CSF clearance pathways for protein removal from the brain, including Aß clearance. Studies have found lipid droplet (LD) accumulation and Aß aggregation together with decreased secretory activity in the CP in ageing/AD. The brain is the most cholesterol-rich organ and altered cholesterol balance has been linked to AD. SOAT1 is an enzyme that converts excess brain cholesterol into cholesterol esters (CEs) for storage as cytoplasmic LDs. Interestingly, Soat1 gene knockout or inhibiting SOAT1 with a compound can reduce Aß aggregation in the hippocampus (a brain region involved in learning and memory) and improve cognitive performance in AD mouse models, suggesting that SOAT1 has the potential to be an AD therapeutic target. Currently, clinical trials of SOAT1 targeting drugs (intended for atherosclerosis) have failed, possibly due to peripheral toxicity. Our preliminary data obtained from mouse models have revealed accumulation of LDs and Aß in CPe in ageing/AD. Moreover, we found that Soat1 gene knockout can markedly alleviate these phenotypes in CP. Given the importance of CP to Aß clearance, we reason that in the CP, SOAT1 can cause LD accumulation in CPe in ageing/AD, leading to CP functional decline and consequently diminished Aß clearance. In this proposal, we hypothesize that repressing CPe SOAT1 function can reduce LD accumulation and thereby enhance Aß clearance from the CP, resulting in a de-ageing/therapeutic effect in ageing/AD. This study will employ a collection of tailored transgenic mice, gene manipulation and cutting-edge omics techniques to investigate the following: 1). The contribution of CPe SOAT1 to AD pathology. 2). AD induction with SOAT1 overexpression in CPe. 3). The influence of SOAT1 on CP’s ability to remove Aß. 4). The effect of targeting CPe Soat1 with gene therapy in AD mice. 5). Lipidomics and transcriptomics analyses of CP in relation to CPe SOAT1’s role in ageing/AD. In summary, our study will unveil the role of CPe SOAT1 in AD pathology and provide robust evidence for assessing the possibility of using CPe SOAT1 as an AD therapeutic target, paving the way for developing novel therapies for AD.
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