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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.

SUBMITTER: Cho JD

PROVIDER: S-EPMC8175658 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.

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

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