Multiphoton in vivo imaging of amyloid in animal models of Alzheimer's disease

Abstract

Amyloid-beta (Abeta) deposition is a defining feature of Alzheimer's disease (AD). The toxicity of Abeta aggregation is thought to contribute to clinical deficits including progressive memory loss and cognitive dysfunction. Therefore, Abeta peptide has become the focus of many therapeutic approaches for the treatment of AD due to its central role in the development of neuropathology of AD. In the past decade, taking the advantage of multiphoton microscopy and molecular probes for amyloid peptide labeling, the dynamic progression of Abeta aggregation in amyloid plaques and cerebral amyloid angiopathy has been monitored in real time in transgenic mouse models of AD. Moreover, amyloid plaque-associated alterations in the brain including dendritic and synaptic abnormalities, changes of neuronal and astrocytic calcium homeostasis, microglial activation and recruitment in the plaque location have been extensively studied. These studies provide remarkable insight to understand the pathogenesis and pathogenicity of amyloid plaques in the context of AD. The ability to longitudinally image plaques and related structures facilitates the evaluation of therapeutic approaches targeting toward the clearance of plaques.

Fig. 1

Methoxy-X04 labeled amyloid plaques and cerebral angiopathy in the barrel cortex of a PS1/APP mouse. Representative Z-series maximum intensity projection of methoxy-X04 labeled amyloid plaques and cerebral amyloid angiopathy in low (a) and high (b) magnification images. Amyloid deposits are labeled with methoxy-X04 (green) and cerebral vasculatures are labeled with rhodamine-dextran (red).

Fig. 2

Age-dependent aggregation of CAA in a vessel segment. Repeated In vivo imaging of a PS1/APP mouse at two weeks intervals from 2 to 6-months of age. Serial imaging of the same volume in barrel cortex exhibited a progressive increase in cerebral amyloid angiopathy (labeled with methoxy-X04, green) in a typical vessel segment which was identified with rhodamine-dextran (red).

Fig. 3

Axon and dendritic abnormalities near amyloid plaques. In vivo time-lapse imaging showed GFP-labeled cortical dendrites and axons near an amyloid plaque in the cortex of a PSAPP/YFP mouse at 6 month of age. Although the majority of spines (arrowheads) and varicosities (asterisks) were stable over 3 days, some structural changes (such as spine loss (arrows) and varicosity formation (double arrows)) did occur. (This figure is reproduced with permission from Tsai et al., 2004).

Fig. 4

Amyloid plaques alter the morphology and trajectory of neurites in vivo. (a and b) Low magnification images exhibit an overview GFP-AAV injection site containing GFP-filled neurites (green), Texas red-labeled vasculature (red), and methoxy-X04 labeled amyloid deposition (blue). (c and d) In higher magnification images, arrows indicate amyloid-associated dystrophic neurites, showing trajectory curves around plaques. (e and f) Three-dimensional reconstructions of plaques and neurites clearly show this curvature around plaques and highlight dystrophies near plaques (arrows). (This figure is reproduced with permission from Spires et al., 2005).