The Role of PTP1B in Anxiety-Related Behaviours in hAPP-J20 and PS19 Mouse Models of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder amongst older adults. Features of this disease include accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles (NFT), neuroinflammation, and neurodegeneration. These result in a progressive decline in memory and executive function in patients. Anxiety-related behaviours are disparaging comorbidities of AD, but how they arise in patients remains elusive. Protein-tyrosine phosphatase 1B (PTP1B) has been associated with Aβ pathology and with anxiety in separate paradigms, but whether PTP1B is involved in anxiety-related behaviours in AD mouse models is unknown. The objective of this project was to compare anxiety-related behaviours between the hAPP-J20 (Aβ pathology) and PS19 (Tau pathology) mouse models of AD and determine whether PTP1B is involved in these behaviours. Another major objective of this project was to investigate the role of PTP1B in tau pathology in the PS19 mouse model in anxiety-related brain regions, since this has not been previously examined. Using key anxiety-testing paradigms such as the elevated plus maze (EPM) and the open field test (OF), an age-based dimorphism in the onset of an inappropriately lowered anxiety response in the J20 and PS19 mouse models was identified. Furthermore, it was shown that this abnormal anti-anxiety baseline phenotype could be normalized with selective PTP1B inhibition by the drug trodusquemine and by genetic neuronal ablation. Finally, in PS19 mice at 8 months of age, it was shown that PTP1B blockade has the therapeutic effect of relieving neurotoxic phospho-tau burden and neuroinflammation. Together, these findings suggest that unleashed PTP1B may serve as a potential therapeutic target, with a possible role in AD-associated anxiety-related behaviours and AD pathology.