BACKGROUND: After age, the second largest risk factor for Alzheimer's disease 
(AD) is apolipoprotein E (APOE) genotype, where APOE4 is associated with lower 
apoE protein levels, more severer brain pathology, enhanced inflammation and 
disease. Small peptides corresponding to the receptor-binding region of apoE 
mimic the anti-inflammatory activity of the apoE holoprotein. These apoE 
mimetics greatly improve behavioral outcomes and neuronal survival in head 
trauma models that display AD pathology and neuronal loss.
OBJECTIVE: To determine whether apoE mimetics change behavior, inflammation and 
pathology in CVND-AD (SwDI-APP/NOS2(-/-)) transgenic mice.
METHODS: Starting at 9 months, apoE peptides were subcutaneously administered 3 
times per week for 3 months followed by behavioral, histochemical and 
biochemical testing.
RESULTS: Treatment with apoE mimetics significantly improved behavior while 
decreasing the inflammatory cytokine IL-6, neurofibrillary tangle-like and 
amyloid plaque-like structures. Biochemical measures matched the visible 
pathological results.
CONCLUSIONS: Treatment with apoE mimetics significantly improved behavior, 
reduced inflammation and reduced pathology in CVND-AD mice. These improvements 
are associated with apoE-mimetic-mediated increases in protein phosphatase 2A 
activity. Testing in additional AD models showed similar benefits, reinforcing 
this novel mechanism of action of apoE mimetics. These data suggest that the 
combination of anti-inflammatory and neuroprotective activities of apoE mimetics 
represents a new generation of potential therapeutics for AD.