The role of apolipoprotein E and lipoprotein receptors in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy

Alzheimer's disease (AD) is characterized by the deposition of the normally soluble amyloid-beta (Abeta) peptide into plaques in brain parenchyma and the walls of cerebral vessels known as cerebral amyloid angiopathy (CAA). Using the APPsw and PDAPP transgenic mouse models of AD, we explored the molecular mechanisms leading to CAA. We found that the APPsw model had a high ratio of Abeta 40:42 and developed substantial CAA and associated hemorrhage while the PDAPP model had a low Abeta 40:42 ratio and developed predominantly parenchymal plaque pathology. However, APPsw or PDAPP mice lacking endogenous murine apoE never developed CAA or associated hemorrhage despite substantial parenchymal plaque deposition in both models. Human apoE4 knock-in mice bred to the APPsw model resulted in an even higher ratio of Abeta 40:42 and these mice developed extensive CAA with almost no parenchymal plaques at 15 months of age. Together these data suggest that apoE isoforms may alter the ratio of Abeta 40:42 and influence whether Abeta will deposit in brain parenchyma vs. cerebral vessels. Additionally, we found that mice lacking the low-density lipoprotein receptor (LDLR) had an elevated level of endogenous murine apoE in brain parenchymal tissue as well as cerebrospinal fluid (CSF). However, the presence or absence of the LDLR in 10-month-old PDAPP mice did not significantly affect Abeta deposition. Further studies will be needed to determine whether LDLR plays a significant role in the pathogenesis of AD or CAA. These data further our understanding of the mechanisms leading to CAA vs. parenchymal plaque deposition as well as the role of apoE and the LDLR in these processes and have important implications for therapies intentionally or unintentionally targeting the processing of the amyloid precursor protein or altering the level of brain apoE.