Marked Mild Cognitive Deficits in Humanized Mouse Model of Alzheimer’s-Type Tau Pathology

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.

Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice

“…In the present study, analyzing hTau mice at one year of age, we detected oligomerization of hyper-phosphorylated Tau, but not yet aggregation of the protein. Consistent with the late onset of AD-like Tau pathology in this particular hTau mouse model 69 , these observations likely reflect early disease conditions. In addition, reduced hTau expression due to a shortening of the transgene array over nineteen years of breeding might contribute to this effect 70 .…”

Behavioral and Neurophysiological Implications of Pathological Human Tau Expression in Serotonin Neurons

“…Overall, these data showed that female ePet1 hTauP301L mice have deficits in cognitive function when compared with female controls, while males do not show differences in spatial working memory when assessed at this time point. Spatial working memory deficits have been demonstrated in mouse models of AD with amyloid or tau pathology. − Moreover, in addition to the higher prevalence of AD in female sex, cognitive impairment associated with AD manifests earlier in women than in men. , Additionally, women have higher levels of tau pathology across numerous brain regions, indicating greater vulnerability of the female sex to tau deposition and accelerated cognitive decline in the earlier stages of the disease . Taken together, we show that 5-HT neuron-specific hTauP301L expression in females results in impaired cognitive decline, while spatial working memory is spared in male mice with 5-HT neuron tau pathology.…”

The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

“…Similar effects have also been observed in hiPSC‐derived neurons, which in addition exhibit changes in the AIS but do not show impairments in neuronal activity 100,189,190 . The expression of all six human TAU isoforms from an artificial chromosome in murine Mapt KO background resulted in increased dendritic localization of TAU, TAU hyperphosphorylation and aggregation, memory deficits, and neuronal loss 191–194 . These phenotypes are likely caused by the imbalance between 3R and 4R expression observed in these animals, which is also associated with several tauopathies 191–194 (see the TAU isoforms in tauopathies section).…”