Protein Tyrosine Phosphatase 1B (PTP1B): A Potential Target for Alzheimer’s Therapy?

Abstract

Despite significant advances in current understanding of mechanisms of pathogenesis in Alzheimer’s disease (AD), attempts at drug development based on those discoveries have failed to translate into effective, disease-modifying therapies. AD is a complex and multifactorial disease comprising a range of aberrant cellular/molecular processes taking part in different cell types and brain regions. As a consequence, therapeutics for AD should be able to block or compensate multiple abnormal pathological events. Here, we examine recent evidence that inhibition of protein tyrosine phosphatase 1B (PTP1B) may represent a promising strategy to combat a variety of AD-related detrimental processes. Besides its well described role as a negative regulator of insulin and leptin signaling, PTB1B recently emerged as a modulator of various other processes in the central nervous system (CNS) that are also implicated in AD. These include signaling pathways germane to learning and memory, regulation of synapse dynamics, endoplasmic reticulum (ER) stress and microglia-mediated neuroinflammation. We propose that PTP1B inhibition may represent an attractive and yet unexplored therapeutic approach to correct aberrant signaling pathways linked to AD.

Impaired insulin signaling and spatial learning in middle-aged rats: The role of PTP1B

“…Aging is the main risk factor for the development of Alzheimer's Disease (AD), and the hippocampus is severely affected in this condition (Fjell et al, 2014;Kawas et al, 2000). Recent studies have shown that some pathogenic process behind aging-induced AD involves hippocampal insulin resistance (de la Monte and Wands, 2008;Lourenco et al, 2013;Vieira et al, 2017). The aging changes are linked to the inflammaging mechanism, which consists of increased levels of inflammatory proteins such as interleukin-1beta (IL1β) and tumor necrosis factor alpha (TNFα) (Franceschi et al, 2000;Giunta et al, 2008).…”

“…Insulin plays a neurogenic, synaptogenic, and memory enhancer role in the hippocampus (Takeda et al, 2011;Vieira et al, 2017). At the molecular level, the appropriate hippocampal insulin signaling turns off several proteins involved in the AD molecular mechanism (Takeda et al, 2011;Vieira et al, 2017).…”

“…Insulin plays a neurogenic, synaptogenic, and memory enhancer role in the hippocampus (Takeda et al, 2011;Vieira et al, 2017). At the molecular level, the appropriate hippocampal insulin signaling turns off several proteins involved in the AD molecular mechanism (Takeda et al, 2011;Vieira et al, 2017). A protein that is downstream to insulin signaling is Glycogen Synthase Kinase 3 beta (GSK3β), which is phosphorylated and inactivated through the Phosphatidylinositol-4,5-bisphosphate 3-kinase (Pi3k)/Protein Kinase B (Akt) pathway (Takeda et al, 2011).…”

“…Several studies demonstrated that inflammation may increase the content of Protein Tyrosine Phosphatase-1B (PTP1B) in important targets of insulin such as skeletal muscle (Ropelle et al, 2006), liver (de Moura et al, 2013), and hypothalamus (Chiarreotto- . Therefore, PTP1B is one of the major tyrosine phosphatases of the Insulin Receptor (IR), the IR Substrate-1 (IRS1), and the Tyrosine Kinase Receptor B (TrkB) (Chiarreotto- de Moura et al, 2013;Ozek et al, 2014;Ropelle et al, 2006;Vieira et al, 2017). Mice lacking PTP1B in the hippocampus present increased learning process evaluated by Barnes Maze test (Fuentes et al, 2012), suggesting the role of this protein as a negative regulator of memory (Vieira et al, 2017).…”

PTP1B inhibitor alleviates deleterious microglial activation and neuronal injury after ischemic stroke by modulating ER stress-autophagy axis via PERK signaling in microglia

“…mRNA levels of IL-1β, IL-6 and TNF-α (relative mRNA expression level: IL-1β, P<0.001; IL-6, P<0.01; TNF-α, P<0.01; all compared to OGD/R groups;Figure 2A-C) in rat primary microglial cells after OGD/R insult. In vivo experiment (outlined inFigure 2D) further showed that intraventricular administration of both 5μM and 10μM of PTP1B inhibitor 30 minutes prior to IR injury effectively decreased the number of activated microglia (CD11b/c+) in rat brain after cerebral IR injury (P<0.001 vs sham group,Figure 2D, E).PTP1B inhibitor attenuated cerebral ischemia/reperfusion-induced overall and microglial endoplasmic reticulum stress in ratEndoplasmic reticulum (ER) stress is involved in microglial activation[17,18,35], and PTP1B recently emerged as an important regulator of ER stress in microglia[36]. To explore the involvement of ER stress pathway in cerebral IR injury and the role of PTP1B inhibitor in modulating microglial ER stress after IR injury, western blot assay was performed (Figure 3A)to detect ER stress proteins in sham surgery group, cerebral IR injury group and IR with PTP1Bsc treatment group in rats.…”