![]() Both restoration of insulin responsiveness and use of insulin therapy can lead to improved cognitive performance. It is now proposed that impairments in brain insulin/IGF signaling is associated with increased accumulation of Aβ, phosphorylated tau, reactive oxygen/nitrogen species, pro-inflammatory and pro-apoptosis molecules ( de La Monte et al., 2009 de La Monte, 2012a, b, 2014). In brain, the insulin/insulin-like growth factor (IGF) signaling is important for neuronal growth, synaptic maintenance and neuroprotection ( Stockhorst et al., 2004 Van Dam and Aleman, 2004). The accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of neurodegenerative diseases. However, recent human and preclinical studies have provided convincing evidence that AD is a degenerative metabolic disease, which is mediated by impairments in brain insulin responsiveness, glucose utilization, and energy metabolism leading to increased oxidative stress, inflammation, and worsening of insulin resistance ( Hoyer, 2002, 2004 Schubert et al., 2004 Rivera et al., 2005 Steen et al., 2005 Watson and Craft, 2006 Craft, 2007 Neumann et al., 2008 Krikorian et al., 2010 Luchsinger, 2010 Baker et al., 2011 Talbot et al., 2012 Butterfield et al., 2014a, b de La Monte, 2014). Over decades, it was hypothesized that neurodegeneration in AD is mainly caused by Aβ accumulation, phosphorylated tau aggregation, and/or neuroinflammation. Although AD was discovered a century ago, the etiology of sporadic AD is not well understood. Familial AD displays early disease onset, whereas sporadic AD cases mostly develop the disorder at an older age ( Cruts and Van Broeckhoven, 1998). The first type is inherited via an autosomal dominant pattern, i.e., familial AD, and the second type is sporadic AD. AD may be classified in two types based on genetic endowment. The main pathological hallmarks of AD are extracellular insoluble beta amyloid (Aβ) plaques ( Selkoe, 1989) and intracellular neurofibrillary tangles (NFTs). The neurodegeneration in AD is characterized by neuronal loss and synaptic injury ( Dekosky and Scheff, 1990). Patients suffering from AD exhibit cognitive impairment, memory loss, and behavioral changes ( Querfurth and Laferla, 2010). AD is a progressive, degenerative, and irreversible neurological disorder that causes deterioration of memory, judgment, and reasoning in the elderly ( Querfurth and Laferla, 2010). ![]() ![]() About 35.6 million people worldwide are now suffering from AD, and disease prevalence is expected to affect 115 million by 2050 ( Wortmann, 2012). Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.Īlzheimer's disease (AD) is the most common cause of dementia. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. In this review we will discuss the role played by aberrant brain insulin signaling in AD. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. 4Department of Clinical and Experimental Medicine, University of Foggia, Foggia, ItalyĪlzheimer's disease (AD) is the most common form of dementia affecting elderly people.3Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. ![]() 2Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy.Erspamer,” Sapienza University of Rome, Rome, Italy 1Department of Physiology and Pharmacology “V.Gaurav Bedse 1,2, Fabio Di Domenico 2, Gaetano Serviddio 3 and Tommaso Cassano 4 *
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