HDL-Mimetic Peptides as Potential Therapeutics for Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, for which there currently exists no approved disease modifying treatment. A number of large scale human clinical studies have confirmed a robust connection between high density lipoprotein (HDL) – known as the ‘good cholesterol’ levels and AD. Low levels of HDL are associated with increased risk and severity of AD. The role of HDL in the brain is not fully established, however, the anti-inflammatory and anti-oxidative properties of HDL are thought to be critical for its beneficial effects. Apolipoprotein E (apoE) is a key constituent of HDL-like particles in the interstitial fluid (ISF) and cerebral spinal fluid (CSF) in the brain. ApoE exists in 3 common variants in the human population (apoE2, E3, and E4), and the apoE4 isoform is the strongest genetic risk factor for AD, accounting for 40-60% of cases. This risk allele is known to increase neuroinflammation and to promote the aggregation and deposition of amyloid beta (Aβ) in the brain, effects which are influenced by the poor lipidation status of apoE4 (incomplete or improper composition of HDL-like particles) in the brain. Previous studies in the laboratory of Dr. Ling Li have shown that overexpression of human apoA-I, the primary apolipoprotein associated with HDL in the periphery, mitigated amyloid pathology and rescued memory deficits in AD mice. However, a full-length, glycosylated protein is extremely difficult and costly to synthesize and to administer. Therefore, the goal of my research was to test the therapeutic potential of small HDL-mimetic peptides, designed to mimic the beneficial function of their parent apolipoproteins, in AD. My studies focused on 4F, an 18 amino acid HDL-mimetic peptide that has been shown to be safe and well tolerated in human clinical trials for cardiovascular disease. I have demonstrated that the lipidation state of apoE is negatively impacted by the addition of aggregated Aβ to astrocytes from mice and humans, in vitro, an effect that is reversed by the addition of 4F. In addition, I confirmed that apoE4 is less lipidated than apoE2 and E3 at baseline, and demonstrated that apoE4 is more susceptible to the detrimental effects of Aβ on lipidation than apoE2. Intriguingly, 4F was able to completely rescue this effect, bringing apoE4 lipidation levels on par with those of apoE2, even in the presence of Aβ. Preliminary in vivo studies in mice expressing the human apoE isoforms and in a mouse model of AD indicate that 4F reduces soluble amyloid levels in the brain and attenuates memory deficits. As chronic neuroinflammation is a key hallmark of AD pathology, another line of my research focused on a small molecule, called Minnelide. Minnelide is a water soluble, pro-drug of triptolide, which is an anti-inflammatory agent that has been shown in Dr. Li’s lab and in other labs to mitigate AD pathology and rescue memory deficits in animal models. Poor solubility hinders this agent’s prospects in the clinic, and so we sought to test the efficacy of Minnelide in AD. My studies show that Minnelide attenuated age-related cognitive decline in AD mice, independent of Aβ levels in the brains of these animals. These data, taken together, indicate that HDL mimetic peptides, and targeting of inflammatory pathways in the periphery and in the brain are promising avenues for continued efforts to find an effective treatment for AD.