Clustering of plaques contributes to plaque growth in a mouse model of Alzheimer’s disease

Abstract

Amyloid-β (Aβ) plaque deposition plays a central role in the pathogenesis of Alzheimer’s disease (AD). Post-mortem analysis of plaque development in mouse models of AD revealed that plaques are initially small, but then increase in size and become more numerous with age. There is evidence that plaques can grow uniformly over time; however, a complementary hypothesis of plaque development is that small plaques cluster and grow together thereby forming larger plaques. To investigate the latter hypothesis, we studied plaque formation in APPPS1 mice using in vivo two-photon microscopy and immunohistochemical analysis. We used sequential pre- and post-mortem staining techniques to label plaques at different stages of development and to detect newly emerged plaques. Post-mortem analysis revealed that a subset (22 %) of newly formed plaques appeared very close (<40 μm) to pre-existing plaques and that many close plaques (25 %) that were initially separate merged over time to form one single large plaque. Our results suggest that small plaques can cluster together, thus forming larger plaques as a complementary mechanism to simple uniform plaque growth from a single initial plaque. This study deepens our understanding of Aβ deposition and demonstrates that there are multiple mechanisms at play in plaque development.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1137-2) contains supplementary material, which is available to authorized users.

Early-onset Formation of Parenchymal Plaque Amyloid Abrogates Cerebral Microvascular Amyloid Accumulation in Transgenic Mice

“…The core/ periphery composition of related, but distinct, A␤ peptides in the parenchymal amyloid plaques of the bigenic Tg-SwDI/Tg5xFAD mice is highly similar to previous findings in mice where one strain of prion protein was shown to form an initial prion plaque core that could act as a scaffold for the aggregation and deposition of another strain of prion protein along the periphery to form hybrid plaques (63). The formation of these small, peripheral satellite plaque deposits of Dutch/Iowa CAA mutant A␤ may further cluster to grow the size of the initial plaque deposit, as shown recently in APP/PS1 mice (64).…”

In vivo imaging reveals sigmoidal growth kinetic of β-amyloid plaques

“…In addition, the arguments (ii) and (iii) may explain negative plaque growth rates in aged animals, whereas we can not completely exclude that at least in part data noise is responsible for negative values. A recent study proposed clustering of plaques as different mechanism of plaque growth [34]. In some rare instances we also observed fusion of plaques which we found as a consequence of their volume growth in combination with close proximity to each other (see image series Figures 1 and 3, Additional file 1).…”

Inhibition of amyloid-β plaque formation by α-synuclein

“…As expected, when we additionally used the monoclonal antibody 4G8 as an alternate staining antibody, similar Aβ staining characteristics were obtained with both antibodies (3552 and 4G8) on brain sections ( Supplementary Fig. 3a,b) 22 and in a dot blot assay from Aβ fibrils generated in vitro in the presence or absence of α-syn (Supplementary Fig. 3c).…”