Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice
Robert P. Brendza, Brian J. Bacskai, John R. Cirrito, Kelly A. Simmons, Jesse M. Skoch, William E. Klunk, Chester A. Mathis, Kelly R. Bales, Steven M. Paul, Bradley T. Hyman, David M. Holtzman
Robert P. Brendza, Brian J. Bacskai, John R. Cirrito, Kelly A. Simmons, Jesse M. Skoch, William E. Klunk, Chester A. Mathis, Kelly R. Bales, Steven M. Paul, Bradley T. Hyman, David M. Holtzman
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Article Neuroscience

Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice

Abstract

Neuritic plaques are a defining feature of Alzheimer disease (AD) pathology. These structures are composed of extracellular accumulations of amyloid-β peptide (Aβ) and other plaque-associated proteins, surrounded by large, swollen axons and dendrites (dystrophic neurites) and activated glia. Dystrophic neurites are thought to disrupt neuronal function, but whether this damage is static, dynamic, or reversible is unknown. To address this, we monitored neuritic plaques in the brains of living PDAPP;Thy-1:YFP transgenic mice, a model that develops AD-like pathology and also stably expresses yellow fluorescent protein (YFP) in a subset of neurons in the brain. Using multiphoton microscopy, we observed and monitored amyloid through cranial windows in PDAPP;Thy-1:YFP double-transgenic mice using the in vivo amyloid-imaging fluorophore methoxy-X04, and individual YFP-labeled dystrophic neurites by their inherent fluorescence. In vivo studies using this system suggest that amyloid-associated dystrophic neurites are relatively stable structures in PDAPP;Thy-1:YFP transgenic mice over several days. However, a significant reduction in the number and size of dystrophic neurites was seen 3 days after Aβ deposits were cleared by anti-Aβ antibody treatment. This analysis suggests that ongoing axonal and dendritic damage is secondary to Aβ and is, in part, rapidly reversible.

Authors

Robert P. Brendza, Brian J. Bacskai, John R. Cirrito, Kelly A. Simmons, Jesse M. Skoch, William E. Klunk, Chester A. Mathis, Kelly R. Bales, Steven M. Paul, Bradley T. Hyman, David M. Holtzman

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Clearance of Aβ deposits by direct application of anti-Aβ antibody to th...
Clearance of Aβ deposits by direct application of anti-Aβ antibody to the surface of the brain. (A) Aβ immunoreactivity in a coronal section from the brain of a PDAPP;YFP double-transgenic mouse that received no treatment. The mouse was fitted with a cranial window on day 0 and sacrificed 7 days later. (B) Aβ immunoreactivity in a coronal section from the brain of a PDAPP;YFP double-transgenic mouse that received treatment with an N-terminal–specific anti-Aβ antibody (20 μg of 10D5). The antibody was administered directly to the surface of the brain, directly under the cranial window, during the surgical procedure on day 0 and sacrificed 7 days later. In both A and B, the area of the brain exposed by the cranial window lies between the arrowheads. (C) A higher magnification of the cortical area exposed by the cranial window in the untreated brain shown in A. (D) A higher magnification of the cortical area exposed by the cranial window in the 10D5-treated brain shown in B. Note the region of reduced Aβ immunoreactivity within 100–200 μm below the cortical surface in the treated area. Scale bars: 250 μm.