Abstract
Tauopathies are a group of disorders leading to cognitive and behavioral impairment in the aging population. While four-repeat (4R) Tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and Alzheimer’s disease, three-repeat (3R) Tau is the most abundant splice, in Pick's disease. A number of transgenic models expressing wild-type and mutant forms of the 4R Tau have been developed. However, few models of three-repeat Tau are available. A transgenic mouse model expressing three-repeat Tau was developed bearing the mutations associated with familial forms of Pick's disease (L266V and G272V mutations). Two lines expressing high (Line 13) and low (Line 2) levels of the three-repeat mutant Tau were analyzed. By Western blot, using antibodies specific to three-repeat Tau, Line 13 expressed 5-times more Tau than Line 2. The Tau expressed by these mice was most abundant in the frontal-temporal cortex and limbic system and was phosphorylated at residues detected by the PHF-1, AT8, CP9 and CP13 antibodies. The higher-expressing mice displayed hyperactivity, memory deficits in the water maze and alterations in the round beam. The behavioral deficits started at 6-8 months of age and were associated with a progressive increase in the accumulation of 3R Tau. By immunocytochemistry, mice from Line 13 displayed extensive accumulation of 3R Tau in neuronal cells bodies in the pyramidal neurons of the neocortex, CA1-3 regions, and dentate gyrus of the hippocampus. Aggregates in the granular cells had a globus appearance and mimic Pick’s-like inclusions. There were abundant dystrophic neurites, astrogliosis and synapto-dendritic damage in the neocortex and hippocampus of the higher expresser line. The hippocampal lesions were moderately argyrophilic and Thioflavin-S negative. By electron microscopy, discrete straight filament aggregates were detected in some neurons in the hippocampus. This model holds promise for better understanding the natural history and progression of 3R tauopathies and their relationship with mitochondrial alterations and might be suitable for therapeutical testing.
Highlights
Taupathies are an important cause of cognitive and behavioral impairment in the aging population [1,2,3]
In the tg mice the bands at 50–55 kDa corresponding to total and 3R Tau co-migrated at levels similar to what it was detected in the Pick's disease (PiD) cases (Fig. 1D-F)
We found that there was a time-dependent increase in accumulation of 3R Tau starting at 6–8 months of age with a concomitant increase in levels of T-Tau and p-Tau (PHF-1) that peaked at 12–14 months of age (Fig. 2A-D)
Summary
Taupathies are an important cause of cognitive and behavioral impairment in the aging population [1,2,3]. Exon 10 of MAPT is alternatively spliced to produce Tau isoforms with either three or four ~32 amino acid repeats, denominated as 3R and 4R Tau, respectively, in the microtubule binding domain of Tau protein [6]. For this reason, tauopathies are divided into those containing 3R, 4R of both species of Tau. Pick's disease (PiD) is a 3R tauopathy, while 4R Tau alone is predominantly present in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Both 3R and 4R Tau are found in Alzheimer’s disease (AD) and FTDP-17T [1]
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