Abstract
Hyperphosphorylation and the subsequent aggregation of tau protein into neurofibrillary tangles (NFTs) are well-established neuropathological hallmarks of Alzheimer’s disease (AD) and associated tauopathies. To further examine the impact and progression of human tau pathology in neurodegenerative contexts, the humanized tau (htau) mouse model was originally created. Despite AD-like tau pathological features recapitulated in the htau mouse model, robustness of behavioral phenotypes has not been fully established. With the ultimate goal of evaluating the htau mouse model as a candidate for testing AD therapeutics, we set out to verify, in-house, the presence of robust, replicable cognitive deficits in the htau mice. The present study shows behavioral data collected from a carefully curated battery of learning and memory tests. Here we report a significant short-term spatial memory deficit in aged htau mice, representing a novel finding in this model. However, we did not find salient impairments in long-term learning and memory previously reported in this mouse model. Here, we attempted to understand the discrepancies in the literature by highlighting the necessity of scrutinizing key procedural differences across studies. Reported cognitive deficits in the htau model may depend on task difficulty and other procedural details. While the htau mouse remains a unique and valuable animal model for replicating late onset AD-like human tau pathology, its cognitive deficits are modest under standard testing conditions. The overarching message is that before using any AD mouse model to evaluate treatment efficacies, it is imperative to first characterize and verify the presence of behavioral deficits in-house.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by cognitive impairment, progressive memory loss, dementia, and behavioral disturbances (Jack et al, 2018)
We confirmed that pathological tau alterations in cortical and hippocampal areas were present in the brains of htau mice; observations that agree with previously published analyses of this mouse (Andorfer et al, 2003), resembling neuropathological features observed in late onset AD brains (Hyman et al, 2012; Montine et al, 2012; DeTure and Dickson, 2019; Figure 1C)
While it is interesting that we found an impaired spatial recognition memory in aged htau mice tested in the Y maze, our study aslo revealed normal Morris Water Maze and fear conditioning performances, adding to the body of existing evidence that failed to show robust cognitive impairments in htau mice (Table 1)
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by cognitive impairment, progressive memory loss, dementia, and behavioral disturbances (Jack et al, 2018). Dysregulation of tau proteostasis can arise from a number of sources such as: splice site and/or missense mutations, changes in overall expression or isoform composition (Trabzuni et al, 2012; Strang et al, 2019), various post-translational modifications (Mair et al, 2016; Arakhamia et al, 2020), and epigenetic regulators (Lardenoije et al, 2015; Millan, 2017) These changes can lead to the abnormal aggregation of tau, resulting in the eventual seeding and spread of pathological tau species that contribute to a number of neurodegenerative diseases, collectively known as tauopathies, which includes AD (Gotz et al, 2019)
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