Neurites containing the neurofilament-triplet proteins are selectively vulnerable to cytoskeletal pathology in Alzheimer’s disease and transgenic mouse models

Matthew T K Kirkcaldie,Tracey C Dickson,Stanislaw Mitew,James C Vickers

doi:10.3389/fnana.2013.00030

Abstract

Amyloid-β plaque accumulation in Alzheimer’s disease (AD) is associated with dystrophic neurite (DN) formation and synapse loss in principal neurons, but interneuron pathology is less clearly characterized. We compared the responses of neuronal processes immunoreactive for either neurofilament triplet (NF+) or calretinin (CR+) to fibrillar amyloid (Aβ) plaques in human end-stage and preclinical AD, as well as in APP/PS1 and Tg2576 transgenic mouse AD models. Neurites traversing the Aβ plaque core, edge, or periphery, defined as 50, 100, and 150% of the plaque diameter, respectively, in human AD and transgenic mouse tissue were compared to age-matched human and wild-type mouse controls. The proportion of NF+ neurites exhibiting dystrophic morphology (DN) was significantly larger than the proportion of dystrophic CR+ neurites in both human AD and transgenic mice (p < 0.01). Additionally, the number of NF+, but not CR+, DNs, correlated with Aβ plaque size. We conclude that CR+ interneurons appear to be more resistant than NF+ neurons to AD-mediated cytoskeletal pathology.

Highlights

Alzheimer’s disease (AD) is commonly associated with a cascade of neuronal cytoskeletal alterations – neurofibrillary tangles (NFTs), neuropil threads and dystrophic neurite (DN) formation, causing spine and synapse loss – as well as overt neuronal degeneration (Spires et al, 2005; Adalbert et al, 2009; Vickers et al, 2009)
The greatest difference between neurofilament triplet proteins (NFs)+ and CR+ neurite responses in all tissue types was in the plaque periphery, where the proportion of DNs was, on average, four times greater for NF+ neurites compared to CR+ (Figures 2–4)
Human AD is characterized by the accumulation of extracellular amyloid β (Aβ) plaques and intracellular NFTs comprised of hyperphosphorylated tau (Braak and Braak, 1991; Braak et al, 2011)

Summary

Introduction

Alzheimer’s disease (AD) is commonly associated with a cascade of neuronal cytoskeletal alterations – neurofibrillary tangles (NFTs), neuropil threads and dystrophic neurite (DN) formation, causing spine and synapse loss – as well as overt neuronal degeneration (Spires et al, 2005; Adalbert et al, 2009; Vickers et al, 2009). These pathological changes develop in a characteristic spatiotemporal progression across the cortex in most human cases (Braak et al, 2011), and to some extent in AD mouse models (Blanchard et al, 2003), suggesting a differential subregional and cellular susceptibility to AD. This progression may imply similar shifts elsewhere in affected neurons

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Conclusion