LRP1 and Alzheimer's Disease
The deposition of amyloid-beta (Abeta) in the brain is considered a critical event in the pathogenesis of Alzheimer's disease. The lab is studying how the low-density lipoprotein receptor-related protein 1 (LRP1), a major receptor for both Abeta and apolipoprotein E (apoE), regulates brain metabolism of Abeta and apoE using in vitro cellular and in vivo animal models.
Using a conditional gene knockout mouse model to delete LRP1 in forebrain neurons, the lab showed that LRP1 regulates brain apoE and cholesterol metabolism, events that are critical for synaptic integrity and function. Using a conditional gene knockout mouse model with the LRP1 gene deleted in specific brain cell types, the lab also found that LRP1 in both neurons and smooth muscle cells plays a critical role in promoting Abeta clearance through receptor-mediated endocytosis and subsequent lysosomal degradation.
The long-term goals of this research are to define the mechanisms by which LRP1 modulates brain Abeta and apoE in cholesterol metabolism — and Abeta oligomerization and accumulation — and to examine how modulation of LRP1 expression in vivo impacts Abeta and apoE in cholesterol during aging and Alzheimer's disease. Several animal models are used for this research.
The lab's working hypotheses are that:
- Abeta accumulation and aggregation in the brain are the initial and seminal events that lead to eventual synaptic deficits and memory impairments in Alzheimer's disease.
- ApoE and apoE receptor LRP1 modulate brain lipid metabolism, synaptic functions and Abeta clearance in an age-dependent manner.
- A decreased LRP level in Alzheimer's disease-affected brains results in compromised apoE in cholesterol metabolism and reduced Abeta clearance, which in turn contributes to synaptic dysfunction and neurodegeneration.