Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.

The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-ß (Aß) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aß levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aß burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aß and amyloid deposition. We further demonstrate that a widespread reduction of brain Aß burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease.

Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aß clearance in a mouse model of ß-amyloidosis.

The apolipoprotein E (APOE)-ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-ß (Aß) accumulation. We recently demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates Aß accumulation by altering Aß clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated Aß clearance, thus leading to reduced Aß accumulation. Using the brain Aß efflux index method, we found that blood-brain barrier-mediated clearance of exogenously administered Aß is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Aß into the plasma of mice using an anti-Aß antibody that prevents degradation of plasma Aß, allowing its rate of appearance from the brain to be measured. Using this plasma Aß accumulation technique, we found that LDLR overexpression enhances brain-to-blood Aß transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Aß clearance, which may serve as a useful therapeutic avenue in targeting Aß clearance from the brain.