Abstract
Neurocognitive disorders, among which Alzheimer’s disease (AD), have become one of the major causes of death in developed countries. No effective disease-modifying therapy is available, possibly because current treatments are administered too late to still be able to intervene in the disease progress. AD is characterized by a gradual onset with subclinical neurobiological and behavioral changes that precede diagnosis with years to even decades. The earlier the diagnosis, the earlier potential treatments can be tested and started. Mouse models are valuable to study the possible causes underlying early phases of neuropathology and their reflection in behavior and other biomarkers, to help improve preclinical detection and diagnosis of AD. Here, we assessed cognitive functioning and social behavior in transgenic mice expressing tau pathology only (Tau-P301L) or a combination of amyloid and tau pathology [amyloid precursor protein (APP)-V717I × Tau-P301L]. The mice were subjected to a variety of behavioral tasks at an age of 3–6 months, i.e., at an early phase of their AD-like pathology. We hypothesized that compared to age-matched wild-type controls, transgenic mice would show specific impairments in both cognitive and non-cognitive tasks. In line with our expectations, transgenic mice showed decreased cognitive flexibility in the Morris water maze, decreased exploratory behavior, decreased performance in a nesting task, and increased anxiety-like behavior. In accordance with the amyloid-cascade hypothesis, some of the behavioral measures showed more severe deficits in APP-V717I × Tau-P301L compared to Tau-P301L mice, indicating an exacerbation of disease processes due to the co-occurrence of amyloid and tau pathology. Our study supports the use of behavioral markers as early indicators of ongoing AD pathology during the preclinical phase.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, accounting for over 70% of all cases (Jaworski et al, 2010), and is estimated to affect over 40 million people worldwide (Selkoe and Hardy, 2016)
Amyloid plaques are mainly composed of Aβ40 and Aβ42 amino acid polypeptides that are derived from the amyloid precursor protein (APP) by proteolytic cleavage
The present study aimed to identify early behavioral and cognitive deficits in two transgenic mouse models of tauopathy and AD, respectively, Tau.P301L and APP.V717I × Tau.P301L mice
Summary
Alzheimer’s disease (AD) is the most common form of dementia, accounting for over 70% of all cases (Jaworski et al, 2010), and is estimated to affect over 40 million people worldwide (Selkoe and Hardy, 2016). Behavioral Deficits in AD neurobiological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (Spires-Jones and Hyman, 2014). Aβ40 seems to have a protective function, as it prevents Aβ42 from aggregating and forming plaques (Götz and Ittner, 2008). NFTs are formed by aggregated tau, a microtubule binding protein that is mainly found in axons, where it stabilizes microtubuli and likely plays a role in cellular transport processes (Spires-Jones and Hyman, 2014). In AD and other tauopathies, tau is hyperphosphorylated and dissociates from the microtubuli, forming NFTs (Götz and Ittner, 2008). Tau is hypothesized to have prion-like seeding characteristics and occurs in different conformational strains, which have been linked to distinct tauopathies (Sanders et al, 2014; Kaufman et al, 2016), but the clinical relevance of this hypothesis remains to be further clarified (Mudher et al, 2017)
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