Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L)

Abstract

Here, we describe the generation of a novel transgenic mouse model of human tauopathy. The rTg(tau P301L )4510 mouse expresses the P301L mutation in tau (4R0N) associated with frontotemporal dementia and parkinsonism linked to chromosome 17. Transgene expression was driven by a forebrain-specific Ca 2ϩ calmodulin kinase II promoter system resulting in high levels of expression in the hippocampus and neocortex. Importantly, transgene expression in this model is induced via the tetracycline-operon responsive element and is suppressed after treatment with doxycycline. Continued transgene expression in rTg(tau P301L )4510 mice results in age-dependent development of many salient characteristics of hereditary human dementia. From an early age, immunohistochemical studies demonstrated abnormal biochemical processing of tau and the presence of pathological conformation-and phosphorylation-dependent epitopes. Neurofibrillary tangle (NFT) pathology was first observed in the neocortex and progressed into the hippocampus and limbic structures with increasing age. Consistent with the formation of NFTs, immunoblots indicated an age-dependent transition of accumulating tau species from Sarkosyl soluble 55 kDa to insoluble hyperphosphorylated 64 kDa. Ultrastructural analysis revealed the presence of straight tau filaments. Furthermore, the effects of tau P301L expression on spatial reference memory were longitudinally tested using the Morris water maze. Compared with nontransgenic age-matched control littermates, rTg(tau P301L )4510 mice developed significant cognitive impairments from 4 months of age. Memory deficits were accompanied by gross forebrain atrophy and a prominent loss of neurons, most strikingly in hippocampal subdivision CA1. Collectively, these data describe a novel transgenic mouse that closely mimics human tauopathy and may represent an important model for the future study of tau-related neurodegenerative disease.

Increased Cerebral Vascular Reactivity in the Tau Expressing rTg4510 Mouse: Evidence against the Role of Tau Pathology to Impair Vascular Health in Alzheimer's Disease

“…Marked cortical atrophy and ventricular enlargement is evident due to tau-induced neurodegeneration as previously described. 11,12 Figure 1. (A) The mean cerebral blood flow (CBF) within a frontal cortical region of interest (ROI) at baseline and during hypercapnia (5% CO 2 , 95% medical air) across the wild-type (WT) (black line) and rTg4510 groups (n = 6).…”

“…To disentangle the contributions of amyloid pathology and tau-driven neurodegenerative processes to compromised vascular health in AD, we used arterial spin labelling (ASL) MRI to image CVR in the rTg4510 model of AD. 12,13 The rTg4510 mouse presents with tau pathology (and marked neurodegeneration) but no irregular Aβ deposition. Our observations were counterintuitive; cortical CVR was not only preserved in regions of tau pathology, but was significantly increased in comparison with litter matched wild-type (WT) controls.…”

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

“…These observations imply that preventing δTau formation could cause behavioral, synaptic and biochemical alterations approximating those observed in some animal models of tauopathy. [45][46][47][48] Therefore, cleavage of Tau at D 421 could represent a mechanism aimed to prevent hyper-phosphorylation and precipitation of Tau.…”

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

“…Tau hyperphosphorylation is a characteristic feature in the brain of AD patients [33] and it contributes to learning and memory deficits [2] . We measured the effects of HN on the tau phosphorylation induced by Aβ and found a significant increase in the pT205, pS262, pS396, and pS404 residues (Fig.…”

“…It is characterized by deposition of amyloid β (Aβ) plaques, accumulation of intracellular neurofi brillary tangles, and regionalized neuronal dysfunction and dendritic degeneration [1][2][3][4] . The clinical manifestations include a progressive deterioration of memory and cognitive disorders [5] .…”