Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy

Abstract

Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

Viral Delivery of Non-Mutated Human Truncated Tau to Neurons Recapitulates Key Features of Human Tauopathy in Wild-Type Mice

“…3B). The morphology of the immunohistochemical labelling resembled pretangles or NFTs, similar to intracellular DC39C+ inclusions found in transgenic mice overexpressing human truncated tau(151-391/3R) [28].…”

“…In agreement with our histological findings of aggregated tau in tissue sections, we observed accumulation of sarkosyl insoluble tau in the hippocampus of wildtype mice injected with AAV-hSyn-htTau. The signal consisted of a double band of truncated tau and was very similar to sarkosyl insoluble tau from the brain stem of transgenic mice overexpressing truncated tau [28] (Fig. 3C).…”

“…Promoting pathways that lead to increased cleavage of tau was associated with accumulation of aggregated tau [14,24]. Overexpression of truncated tau in both transgenic mice and rats led to neurofibrillary pathology and functional deficits [25][26][27][28]. These studies therefore indicate that truncated tau protein may be critically involved in the pathological process of tau aggregation.…”

FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease

“…Transgenic R3/m4 mice ( n = 10, female, aged ~ 3 months) expressing human truncated tau 151–391/4R under the Thy1 promoter [ 33 ] were housed under standard laboratory conditions, with a 12-h/12-h light/dark cycle, and access to food and water ad libitum . Animals were treated with five doses of AADvac1 (40 μg of Axon Peptide 108 coupled to KLH) in 21-day intervals.…”

Tau Diagnostics and Clinical Studies

“…Notably, sodium 4-phenylbutyrate is a well-known histone deacetylase inhibitor and chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Another transgenic mouse expressing tau 151-391 developed hyperphosphorylated and aggregated tau species, deficits in locomotor activity, and had a reduced lifespan (Zimova et al 2016). Recently, a study characterizing tau CTFs in 12 cortical samples from both control and late Braak stage AD, led to the identification of 21 novel tau fragments (Derisbourg et al 2015).…”