Propagation of Tau Pathology in a Model of Early Alzheimer's Disease

Abstract

Summary Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer disease (AD) evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and co-aggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

“…78,79 However, considered together with the early appearance of Ab relative to p-tau, the marked increase in p-tau in individual Ab-positive synapses is consistent with a hypothesis that p-tau induction is directly driven by synaptic oAb; synaptic p-tau may then lead to anterograde and retrograde trans-synaptic spread of tau pathology. Such a hypothesis is supported by the following multiple lines of evidence: i) the exclusive initial appearance of Ab in the neocortex before dementia onset, which has extensive reciprocal projections with hippocampus and entorhinal cortex 48,80 ; ii) the well-established regional propagation of tau pathology in human disease and animal models 79,81e83 ; iii) the observation that low…”

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

“…Even though OPCs from P301S‐htau mice contained no human tau, their functionality may be influenced by exposure to the transgenic protein in vivo , which has been shown to be released by tau‐overexpressing neurons (de Calignon et al, 2012). To test this hypothesis, we exposed OPCs isolated from Wt mice to filamentous and hyperphosphorylated tau obtained by sarkosyl extraction of spinal cords of 5‐month‐old P301S‐htau mice as previously described (Goedert and Jakes, 1990).…”

Alzheimer disease

“…36,38 Both groups targeted expression of a human tau transgene specifically in the EC of mice. In both cases, the transgene encoded tau three months of age.…”

“…In contrast to PrP-based disorders, such as mad cow disease, scrapie and kuru, AD does not appear to be communicable between individuals, but a growing body of data indicate that misfolded, toxic oligomers of Aβ and tau spread through the brain from neuron to nearby neuron much like misfolded PrP. [25][26][27][28][29][30][31][32] For both Aβ 8,33 and tau, [34][35][36][37][38] moreover, misfolded forms of the peptide or protein can be taken up by neurons containing otherwise normal Aβ or tau, which as a result then misfold, become toxic and spread to other neurons.…”

“…In addition to in vivo histopathology evidence, 33,35,36,38 several groups recently demonstrated biochemical mechanisms for prion-like propagation of Aβ and tau, 9,39-42 and of additional…”