Ambiguous Effects of Prolonged Dietary Supplementation with a Striatal-Enriched Protein Tyrosine Phosphatase Inhibitor, TC-2153, on a Rat Model of Sporadic Alzheimer\u2019s Disease

E A Rudnitskaya,A O Burnyasheva,D V Telegina,K P Volcho,N A Muraleva,T M Khomenko,N G Kolosova,T A Kozlova,N F Salakhutdinov

doi:10.1134/s1819712421030090

Abstract

Alzheimer’s disease (AD) is the most common type of dementia and is currently incurable. After unsuccessful attempts to create drugs targeting the amyloid-β pathway, a search for alternative approaches and treatments targeting nonamyloid AD pathologies is currently underway. One of them is inhibition of striatal-enriched protein tyrosine phosphatase (STEP) activity, which is increased in the prefrontal cortex of AD patients. Here we examined effects of prolonged treatment of OXYS rats which mimic key signs of sporadic AD with a STEP inhibitor, TC-2153, on the progression of signs of AD. TC-2153 had an ambiguous effect on the behavior of the animals: it significantly reduced the already low locomotor and exploratory activities and enhanced anxiety-related behavior in OXYS rats but improved their long-term memory in the Morris water maze. Moreover, TC-2153 had no effect on the accumulation of the amyloid-β protein and on the STEP61 protein level; the latter in the cortex and hippocampus did not differ between OXYS rats and control Wistar rats. These results suggest that the effects of prolonged treatment with TC-2153 may be mediated by mechanisms not related to STEP. In particular, TC-2153 can act as a potential hydrogen sulfide donor and thus substantially affect redox homeostasis.

Highlights

Alzheimer’s disease (AD) is a progressive incurable age-related neurodegenerative disorder in the elderly and the most prevalent cause of dementia [1, 2]
As reported [5], brief treatment with TC2153 is effective in reversing cognitive and memory deficits in a transgenic mouse model of AD (3xTg-AD mice) but does not affect Aβ and tau brain pathology of these animals. These results suggest that striatalenriched tyrosine protein phosphatase (STEP) is a potential target for AD drug discovery
TC-2153 treatment decreased the time spent in open arms of the maze by OXYS rats (p < 0.02; the Newman–Keuls test), causing an increase in anxiety; the parameter did not differ between TC-2153-treated OXYS rats and control Wistar rats

Summary

Introduction

Alzheimer’s disease (AD) is a progressive incurable age-related neurodegenerative disorder in the elderly and the most prevalent cause of dementia [1, 2]. During the last three decades, targeting the amyloid-β (Aβ) pathway has been central to the search for effective treatments; none of the clinical trials targeting Aβ culmi-. Given the complexity of AD pathology and progression, an active search for treatments targeting nonamyloid AD pathologies and for alternative approaches is currently underway. After the finding of elevated striatalenriched tyrosine protein phosphatase (STEP) activity in the prefrontal cortex of human AD patients and in mouse models of AD, modulation of STEP levels or inhibiting its activity are considered one of the promising approaches to the development of a new family of novel therapeutic approaches to this disease [5, 6]

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