High plasticity of axonal pathology in Alzheimer’s disease mouse models

Abstract

Axonal dystrophies (AxDs) are swollen and tortuous neuronal processes that are associated with extracellular depositions of amyloid β (Aβ) and have been observed to contribute to synaptic alterations occurring in Alzheimer’s disease. Understanding the temporal course of this axonal pathology is of high relevance to comprehend the progression of the disease over time. We performed a long-term in vivo study (up to 210 days of two-photon imaging) with two transgenic mouse models (dE9xGFP-M and APP-PS1xGFP-M). Interestingly, AxDs were formed only in a quarter of GFP-expressing axons near Aβ-plaques, which indicates a selective vulnerability. AxDs, especially those reaching larger sizes, had long lifetimes and appeared as highly plastic structures with large variations in size and shape and axonal sprouting over time. In the case of the APP-PS1 mouse only, the formation of new long axonal segments in dystrophic axons (re-growth phenomenon) was observed. Moreover, new AxDs could appear at the same point of the axon where a previous AxD had been located before disappearance (re-formation phenomenon). In addition, we observed that most AxDs were formed and developed during the imaging period, and numerous AxDs had already disappeared by the end of this time. This work is the first in vivo study analyzing quantitatively the high plasticity of the axonal pathology around Aβ plaques. We hypothesized that a therapeutically early prevention of Aβ plaque formation or their growth might halt disease progression and promote functional axon regeneration and the recovery of neural circuits.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0415-y) contains supplementary material, which is available to authorized users.

Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques

“…To this end, we counted the number of β -amyloid plaques above the threshold diameter of 9.9 µm in three LEC and three HC sections in each mouse, yielding 58-119 plaques per mouse in LEC and 47 -84 plaques per mouse in HC. Recent evidence suggests that the number of dystrophic neurites around β -amyloid plaques in transgenic APP mice increases with the plaque diameter [5]. We found a similar relationship between the plaque diameter and the number of neurites both in LEC (R 1923 = 0.28, p < 0.001) and HC (R 1467 = 0.36, p < 0.001) (data not shown).…”

Simulated spatial radiation impacts learning and memory ability with alterations of neuromorphology and gut microbiota in mice

“…40 Mitochondrial dysfunction is a common feature in neurodegenerative disease, including Alzheimer's and Parkinson's disease. [41][42][43] Therefore, the observed ultrastructural defects in the hippocampus may be related to the decits in learning and memory induced by 60 Co-g irradiation. Other rays at different doses have also been observed to cause similar hippocampal decits in mice and rats.…”

JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

“…The massive accumulation of these organelles at the distal side of focal blocks of axonal transport reveals that such lysosomes are the major retrograde axonal cargo (Tsukita and Ishikawa, 1980). A similar build-up of immature lysosomes is observed in axon swellings surrounding amyloid Aβ deposits at Alzheimer's disease amyloid plaques (both in human patients and in mouse models of the disease), which are putative sites of APP processing (Blazquez-Llorca et al, 2017;Gowrishankar et al, 2015;Nixon, 2005). A link between accumulation of axonal lysosomes due to their impaired transport and amyloidogenic APP processing was further supported by studies of neurons and mice with loss of JIP3 function (Gowrishankar et al, 2017).…”