AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.
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.
Kiyota
Tomomi
T
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA.
Yamamoto
Masaru
M
Schroder
Bryce
B
Jacobsen
Michael T
MT
Swan
Russell J
RJ
Lambert
Mary P
MP
Klein
William L
WL
Gendelman
Howard E
HE
Ransohoff
Richard M
RM
Ikezu
Tsuneya
T
D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000686:Amyloidosis / Q000628:therapy*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics* / Q000502:physiology; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D005911:Gliosis / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018932:Chemokine CCL2; D053764:Presenilin-1