Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease.
Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the epsilon4 allele increasing and the epsilon2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-beta peptide (Abeta) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Abeta and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Abeta(1-42) levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Abeta burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Abeta burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Abeta burden and the subsequent development of neuritic plaques.
Dodart
Jean-Cosme
JC
Neuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Marr
Robert A
RA
Koistinaho
Milla
M
Gregersen
Beth M
BM
Malkani
Seema
S
Verma
Inder M
IM
Paul
Steven M
SM
D000544:Alzheimer Disease / Q000378:metabolism / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D053329:Apolipoprotein E2; D001057:Apolipoproteins E