Hyperphosphorylated tau and paired helical filament-like structures in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes

• Published in: Neurobiology of disease 2003-10, Vol.14 (1), p.89-97
• Main Authors: Kurt, M.A, Davies, D.C, Kidd, M, Duff, K, Howlett, D.R
• Format: Article
• Language: English
• Subjects: Adult; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Brain - metabolism; Brain - pathology; Dystrophic neurites; Humans; Hyperphosphorylated tau; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Middle Aged; Mutation; Neurofibrillary tangles; Paired helical filaments; Phosphorylation; Presenilin-1; tau Proteins - genetics; tau Proteins - metabolism; Transgenes - physiology; Transgenic mouse brain; β-Amyloid
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/S0969-9961(03)00084-6

Senile plaques composed mainly of β-amyloid (Aβ) and neurofibrillary tangles principally composed of hyperphosphorylated tau are the major pathological features of Alzheimer’s disease (AD). Despite the fact that increased expression of amyloid precursor protein (APP) and presenilin-1 (PS1) transgenes in mice lead to increased Aβ deposition in plaquelike structures in the brain, little is known about the nature and distribution of tau in these mice. Therefore the relationship between Aβ and hyperphosphorylated tau was investigated in mice carrying mutant APP and mutant PS1 transgenes using both light (LM) and electron microscopy (EM) with immunocytochemistry. LM immunocytochemistry revealed cerebral Aβ deposits to be present from 8 weeks of age, whereas hyperphosphorylated tau was not detected until 24 weeks of age, when it appeared as punctate deposits in close association with the Aβ deposits in the cortex and hippocampus. However, dystrophic neurites were not as heavily immunolabeled as they are in AD brain. EM revealed that aggregations of straight filaments (10–12 nm wide) were present in some cellular processes at the periphery of Aβ plaques in 8-month-old APP/PS1 mice. In one such mouse, single filaments and paired filaments showing a helical configuration (50–55 nm half-period, 25 nm max. width) were present in a dark, atrophic hippocampal neuron. Immunogold labeling of APP/PS1 mouse brain revealed hyperphosphorylated tau epitopes in some dystrophic neurites from 24 weeks of age that were similar to those present in AD. These results suggest that hyperphosphorylated tau appears in APP/PS1 mouse brain after the onset of Aβ depositition and although it is associated with Aβ deposits, its distribution is not identical to that in AD.