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Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches

Abstract

Amyloid plaques are a hallmark of Alzheimer disease, but their importance in its pathogenesis is controversial. By neuronal labeling and transcranial two-photon imaging, we show in a transgenic mouse model of Alzheimer disease that dendrites passing through or near fibrillar amyloid deposits undergo spine loss and shaft atrophy, and nearby axons develop large varicosities, together leading to neurite breakage and large-scale, permanent disruption of neuronal connections. Thus, fibrillar amyloid deposition is more detrimental to neuronal circuitry than previously thought, underscoring the importance of prevention and early clearance of plaques.

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Figure 1: Dendritic and axonal abnormalities occur inside and within 15 μm of fibrillar Aβ deposits.
Figure 2: Axonal and dendritic abnormalities near fibrillar deposits occur progressively over days to weeks.
Figure 3: Neurite breakage occurs within and near fibrillar Aβ deposits.

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Acknowledgements

We thank S. Burden and T. Wisniewski for critical comments on the manuscript. We also thank Y. Matsuoka for his assistance in the initial experiments. This work was supported by grants from the US National Institutes of Health and the Alzheimer's Disease Foundation to W.-B.G.

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Correspondence to Wen-Biao Gan.

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Supplementary information

Supplementary Fig. 1

Defining the boundary of fibrillar amyloid deposits. Defining the boundary of fibrillar amyloid deposits. (1) One cross section of a fibrillar amyloid deposit that was labeled with Congo Red and imaged with two-photon microscopy in vivo. (2) A fluorescence intensity profile of the fibrillar amyloid along a line in (1). The boundary of the amyloid deposit was determined as the cross point of the two trend lines representing a slow rise and a sharp rise in fibrillar amyloid intensity. (PDF 151 kb)

Supplementary Fig. 2

Development of dendritic and axonal abnormalities inside and near fibrillar amyloid deposits (1). Dendrites passing through and in close proximity to fibrillar amyloid undergo spine loss, shaft atrophy (2) and eventual breakage (3). Axons near amyloid deposits form abnormally varicosities (2) and eventually undergo breakage (3). These local dendritic and axonal abnormalities could cause permanent and global disruption of communication between the distal and proximal segments of dendrites and axons located within and near amyloid deposits. (PDF 121 kb)

Supplementary Methods (PDF 37 kb)

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Tsai, J., Grutzendler, J., Duff, K. et al. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7, 1181–1183 (2004). https://doi.org/10.1038/nn1335

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