Small HDL particles in brain appear protective against Alzheimer’s disease
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Key takeaways:
- A gene present in 25% of the population, which reduces neuroprotective small HDL production, is associated with increased Alzheimer’s disease risk.
- A drug in early development may be the key to lowering risk.
Small HDL particles play a significant role in the prevention of Alzheimer’s disease, and an inherited gene present in one in four people hinders its production in the brain, increasing risk for cognitive decline, a speaker reported.
New therapeutics in development could improve lipidation and the production of cerebral small HDL particles, but crossing the blood-brain barrier remains a challenge, according to a presentation at the World Congress Insulin Resistance Diabetes & Cardiovascular Disease Conference.
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“Up to 5 million to 6 million Americans will have Alzheimer’s disease. The fundamental hallmarks of how we make that diagnosis is based on accumulation of amyloid plaques and tau tangles. Advances in PET imaging has allowed us to make biomarkers accessible to living people,” Hussein N. Yassine, MD, the Kenneth and Bette Volk endowed chair of neurology at the University of California, Keck School of Medicine, said during a presentation. “At the moment, the diagnosis of Alzheimer’s disease is getting more and more precise with plasma [Alzheimer’s disease] biomarkers and so forth.”
Yassine said presence of the apolipoprotein E (ApoE) epsilon 4 allele is significantly associated with risk for developing Alzheimer’s disease. With a population prevalence of one in four people, inheritance of the ApoE4 gene from one parent is tied to an up to fourfold increased risk for Alzheimer’s disease, and inheritance from both parents is tied to an up to 10-fold increased risk.
In the brain, apolipoprotein is lipidated to form HDL-like peptides, which are not the same as HDL cholesterol, and starts with a lipid-free ApoA-I or lipid-free ApoE.
After interacting with a transporter known as ATP-binding cassette transporter A1 (ABCA1), a prebeta-1 particle, or very small HDL particle, is created. Remodeling by ABCA1, ATP-binding cassette transporter GI (ABCG1), scavenger receptor type B class I (SR-B1) and lecithin-cholesterol acyltransferase (LCAT) forms small HDL, or HDL3. After further remodeling with LCAT and cholesteryl ester transfer protein (CETP), larger HDL particles — HDL2 — are created, according to the presentation.
“The reason why this is important for Alzheimer’s disease is because if you actually knock out ABCA1 in Alzheimer’s disease models, you accumulate amyloid. ... So it’s not just making lipids. The process of making lipids is also involved in the process of accumulating amyloid in the brain,” Yassine said. “ABCA1 is very important. It doesn’t show up on [genome-wide association studies] because of how important it is, but there has been very close detailed, population studies and the very rare loss-of-function mutations in ABCA1 are associated with an increased risk of Alzheimer’s disease.”
A prior study published in Alzheimer’s & Dementia demonstrated that individuals with cognitive impairment had lower levels of ABCA1 activity of cerebral spinal fluid compared with patients with normal cognitive function.
Citing findings from another study published in the Journal of Neuroscience, Yassine said ApoE aggregation caused by the presence of the ApoE epsilon 4 allele impairs the expression and activity of ABCA1 by trapping the transporter within late endosomes and lysosomes.
“Interestingly, the amount of small HDL particles in [cerebral spinal fluid] were significantly correlated with [cerebrospinal fluid beta-amyloid 42],” Yassine said. “The higher the [cerebrospinal fluid beta-amyloid 42], the less plaques there are. ... So this means more small HDL particles is associated with less amyloid plaques in the brain. This correlation was weaker with large HDL.
“Moreover, when you look at cognitive measures, whether it’s memory, executive function or global cognition, there is a weak but significant correlation between small HDL particles, their concentration in [cerebrospinal fluid] and measures of cognition,” he said.
Based on those findings, Yassine and colleagues developed the ABCA1 agonist CS-6253 — a peptide drug that generates small HDL — from ApoE to protect from ABCA1 degradation and potentially lower risk for Alzheimer’s disease in people with the APOE epsilon 4 allele.
Their initial findings, published in Alzheimer’s Research and Therapy, demonstrated increased plasma prebeta-1 HDL and improved plasma beta-amyloid 42/40 ratio, as a surrogate to brain beta-amyloid 42 clearance, in monkeys. This resulted in increased plasma ApoE.
The researchers reported that, unfortunately, CS-6253 was unable to penetrate the blood-brain barrier.
However, Yassine said research led by Juno S. Van Valkenburgh, PhD, a postdoctoral scholar and research associate at the University of Southern California, Keck School of Medicine, produced a potential solution by coupling a reversed CS-6253 with an angiopep brain delivery peptide.
“Small HDL particles have neuroprotective roles against Alzheimer’s disease pathology. Brain ABCA1 activity is important and drives the formation of small HDL, which is lower in patients with Alzheimer’s disease. ApoE epsilon 4 aggregates and impairs ABCA1 ApoE lipidation recycling of HDL particles,” Yassine said. “Developing therapeutic strategies based on this concept is challenging, but we’re doing the best we can and hopefully we can get something that can get into brain.”
References:
- Martinez AE, et al. Alzheimers Dement. 2022;doi:10.1002/alz.12649.
- Noveir SD, et al. Alzheimers Res Ther. 2022;doi:10.1186/s13195-022-01028-1.
- Rawat V, et al. J Neurosci. 2019;doi:10.1523/JNEUROSCI.1400-19.2019.
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Yassine HN. Brain HDL and Alzheimer’s disease: Toward therapeutic applications. Presented at: World Congress Insulin Resistance Diabetes & Cardiovascular Disease Conference; Dec. 7-9, 2023; Los Angeles.
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