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.1 Dr. Bu's laboratory has been studying how a major apolipoprotein E (apoE) receptor, low-density lipoprotein receptor-related protein 1 (LRP1), regulates Abeta production and clearance in vitro and in vivo.
The lab generated transgenic mice that overexpress a minireceptor form of LRP1 in the brain. These mice were bred with Alzheimer's disease model mice, PDAPP, which overexpress a mutant form of human amyloid precursor protein (APP) and develop Alzheimer's disease-like amyloid plaques. The lab found that PDAPP/LRP1 double-transgenic mice exhibit a significant age-dependent increase of soluble Abeta, resulting in enhanced deficits in spatial learning and memory.2
Using a conditional gene knockout mouse model to delete LRP1 in the forebrain, the lab showed that LRP1 regulates brain apoE and cholesterol metabolism. Further, APP processing product, amyloid precursor protein intracellular domain (AICD), regulates LRP1 expression by binding directly to LRP1 promoter.3
In addition, Dr. Bu's group found that neuronal LRP1 functions together with cell surface heparan sulfate proteoglycan to mediate Abeta uptake, trafficking and eventual delivery to lysosomes.4
The long-term goals of this research focus are to define the mechanisms by which LRP1 modulates brain Abeta and apoE/cholesterol metabolism — and Abeta oligomerization and accumulation — and to examine how modulation of LRP1 expression in vivo impacts Abeta and apoE/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/cholesterol metabolism and reduced Abeta clearance, which in turn contributes to synaptic dysfunction and neurodegeneration.
- Bu G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009 May;10(5):333-44. PMID: 19339974
- Zerbinatti CV, Wozniak DF, Cirrito J, Cam JA, Osaka H, Bales KR, Zhuo M, Paul SM, Holtzman DM, Bu G. Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein. Proc Natl Acad Sci USA. 2004 Jan 27;101(4):1075-80. PMID: 14732699
- Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, Bu G. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron. 2007 Oct 4;56(1):66-78. PMID: 17920016
- Kanekiyo T, Zhang J, Liu Q, Liu CC, Zhang L, Bu G. Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake. J Neurosci. 2011 Feb 2;31(5):1644-51. PMID: 21289173