Adult-onset focal expression of mutated human tau in the hippocampus impairs spatial working memory of rats

Abstract

Tauopathy in the hippocampus is one of the earliest cardinal features of Alzheimer’s disease (AD), a condition characterized by progressive memory impairments. In fact, density of tau neurofibrillary tangles (NFTs) in the hippocampus strongly correlates with severity of cognitive impairments in AD. In the present study, we employed a somatic cell gene transfer technique to create a rodent model of tauopathy by injecting a recombinant adeno-associated viral vector with a mutated human tau gene (P301L) into the hippocampus of adult rats. The P301L mutation is causal for frontotemporal dementia with parkinsonism-17 (FTDP-17), but it has been used for studying memory effects characteristic of AD in transgenic mice. To ascertain if P301L-induced mnemonic deficits are persistent, animals were tested for 6 months. It was hypothesized that adult-onset, spatially restricted tau expression in the hippocampus would produce progressive spatial working memory deficits on a learned alternation task. Rats injected with the tau vector exhibited persistent impairments on the hippocampal-dependent task beginning at about 6 weeks post-transduction compared to rats injected with a green fluorescent protein vector. Histological analysis of brains for expression of human tau revealed hyperphosphorylated human tau and NFTs in the hippocampus in experimental animals only. Thus, adult-onset, vector-induced tauopathy spatially restricted to the hippocampus progressively impaired spatial working memory in rats. We conclude that the model faithfully reproduces histological and behavioral findings characteristic of dementing tauopathies. The rapid onset of sustained memory impairment establishes a preclinical model particularly suited to the development of potential tauopathy therapeutics.

Next generation tau models in Alzheimer's disease research – virus based gene delivery systems

“…This effect was not observed using equal doses of green fluorescent protein (GFP) or alpha-synuclein vectors suggesting that the pathological effect is highly specific to misfolded tau neurotoxicity. Expression of AAV9 P301L tau in hippocampus impaired spatial memory and learning (Mustroph et al, 2012). Interestingly, gliosis was also observed at the sites of injection.…”

“…However, recombinant AAVs are infectious, but lack virulency and thus provide a platform for sustainable transgene expression in several animal models (Li et al, 2003;Wu et al, 2006). Recombinant AAVs offer broad range of infectious properties that target different cell types and mechanisms in rodents and humans (Bourdenx et al, 2014;Murlidharan et al, 2014;Shevtsova et al, 2005).…”

“…Thirteen different serotypes of AAVs and their different tropism have been currently well defined (Handa et al, 2000, Gao et al, 2002Cearley and Wolfe, 2006;Zincarelli et al, 2008;Aschauer et al, 2013). The AAV serotypes vary in their origin (Wu et al, 2006), genome sequence, capsid protein (Choi et al, 2005;van Vliet et al, 2008), transduction properties based on proteoglycan binding and glycan modifications (Summerford and Samulski, 1998;Walters et al, 2001;Nonnenmacher and Weber, 2012;Holehonnur et al, 2014;Murlidharan et al, 2014; Table 1) and efficiency of transgene expression (Gao et al, 2002). Mainly in the central nervous system, the AAV serotypes differentially transduce and express proteins, and also vary in their mechanisms of axonal transport (Salegio et al, 2013;Aschauer et al, 2013; Table 1).…”

“…Numerous other AAV-tau models have been developed under different genetic background (Table 2). Most of these models build up AT8 positivity (Klein et al, 2005;Ramirez et al, 2011;Dassie et al, 2013;Asai et al, 2015), neurofibrillary tangles (Klein et al, 2006;de Calignon et al, 2010;Ramirez et al, 2011), degenerating and dystropic neurites (Jaworski et al, 2009(Jaworski et al, , 2011, motor impairment (Klein et al, 2008;Cook et al, 2015), synaptic deterioration (Jaworski et al, 2011;Siman et al, 2013;Yang et al, 2015;Cook et al, 2015) and loss of neurons (Klein et al, 2005(Klein et al, , 2008Jaworski et al, 2011;Mustroph et al, 2012;Dassie et al, 2013;Yang et al, 2015) implicating that AAV vectors can be used to generate rodent models in a short span of time which are efficient (transduction and level of expression) and imitate early and progressive pathological changes as in AD and other tauopathies.…”

Attenuation of Spatial Memory Impairment in a Tau Mouse Model of Alzheimer's Disease with Riluzole

“…Mice lacking specific subunits of NMDA receptors in the hippocampus exhibit impaired working memory, but normal reference memory (Bannerman et al, 2008;Niewoehner et al, 2007). This coincides with findings of impaired working memory functioning in mouse and rat models of AD (Cotel et al, 2012;Mustroph et al, 2012). However, knocking out the APOE gene, using APOE KO mice, improves reference memory compared to controls, without affecting working memory (Avdesh et al, 2011).…”