Research

Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage

Donna M Wilcock¹ , Amyn Rojiani² , Arnon Rosenthal³ , Sangeetha Subbarao³ , Melissa J Freeman¹ , Marcia N Gordon¹ and Dave Morgan¹

¹Alzheimer's Research Laboratory, University of South Florida, Department of Pharmacology, 12901 Bruce B Downs Blvd, Tampa, Florida 33612, USA

²Alzheimer's Research Laboratory, University of South Florida, Department of Interdisciplinary Oncology, 12901 Bruce B Downs Blvd, Tampa, Florida 33612, USA

³Rinat Neuroscience Corp., 3155 Porter Drive, Palo Alto, California 94304, USA

author email corresponding author email

Journal of Neuroinflammation 2004, 1:24doi:10.1186/1742-2094-1-24

Published:	8 December 2004

Abstract

Background

Anti-Aβ immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Aβ antibodies to 19- and 23-month old APP-transgenic mice.

Methods

We investigated the effects of weekly anti-Aβ antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing.

Results

After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Aβ immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy.

Conclusions

The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage.