Accumulation of aggregated
amyloid-beta (Abeta)
peptide was studied as an initial step for
Alzheimer's disease (AD) pathogenesis. Following
amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause
neuroinflammation. Here brain
chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of
chemokine CCL2 in the brain results in increased microglial accumulation and diffuse
amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish
amyloid precursor
protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose-response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without
neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/
presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, beta-
amyloidosis, including suppression of both fibrillar and oligomer Abeta accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related
neuroinflammation.