A limited role for microglia in antibody mediated plaque clearance in APP mice.
Amyloid-beta (Abeta) accumulation in senile plaques is a hallmark of Alzheimer's disease (AD). Immunotherapy is a leading approach for amyloid clearance, despite the early termination of the Elan clinical trial with active immunization due to a few cases of meningoencephalitis. The mechanisms of immunotherapy-mediated amyloid clearance and this deleterious side effect are largely unknown. While clearance of Abeta probably results in part from microglia-mediated inflammation, it can be microglia independent. Therefore, establishing the role of microglia in Abeta clearance is important for the treatment of AD. We analyzed the effects of direct microglia activation and inhibition on antibody-mediated Abeta clearance. Robust microglia activation with interferon-gamma led to modest Abeta clearance alone but did not potentiate antibody-mediated clearance. Microglia elimination/inactivation with immunotoxin or minocycline only partially limited antibody-induced Abeta clearance suggesting that although there is a role for microglia in Abeta clearance, it does not account for the majority of the effect observed after anti-Abeta antibody treatment.
Garcia-Alloza
Monica
M
Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, 114 16th Street, #2010, Charlestown, MA 02129, USA.
Ferrara
Brian J
BJ
Dodwell
Sarah A
SA
Hickey
Gregory A
GA
Hyman
Bradley T
BT
Bacskai
Brian J
BJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002452:Cell Count; D004195:Disease Models, Animal; D004347:Drug Interactions; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors