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.
Highlights
There are currently no disease-modifying therapies for Alzheimer’s disease (AD), and treatments offer limited, temporary improvement in quality of life (Rafii and Aisen, 2015)
Increased protein tyrosine phosphatase 1B (PTP1B) activity is associated with defective neuronal insulin and leptin signaling (Zabolotny et al, 2002; Pandey et al, 2013, 2014), pathways that are impaired in AD (Bomfim et al, 2012; Bonda et al, 2014)
PTP1B-null mice are resistant to weight gain induced by high-fat diet (HFD) or by deletion of the leptin gene, suggesting PTP1B inhibition as a strategy to rescue leptin signaling in food intake disorders and obesity (Elchebly et al, 1999; Cheng et al, 2002)
Summary
There are currently no disease-modifying therapies for Alzheimer’s disease (AD), and treatments offer limited, temporary improvement in quality of life (Rafii and Aisen, 2015). Increased PTP1B activity is associated with defective neuronal insulin and leptin signaling (Zabolotny et al, 2002; Pandey et al, 2013, 2014), pathways that are impaired in AD (Bomfim et al, 2012; Bonda et al, 2014). PTP1B is up-regulated by endoplasmic reticulum (ER) stress (Agouni et al, 2011; Popov, 2012; Hakim et al, 2015), a neuronal response activated by AβOs and implicated in synapse loss and cognitive decline in AD (Kam et al, 2013; Lourenco et al, 2013). Inhibiting PTP1B appears as a promising, yet neglected strategy to combat multiple aspects of AD
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