Invited reviewEvidence for altered insulin receptor signaling in Alzheimer's disease
Introduction
Metabolic diseases (e.g., obesity, metabolic syndrome, type 2 diabetes) are known to increase the propensity for developing cognitive decline and dementia (Arvanitakis et al., 2004, Biessels and Reagan, 2015, Leibson et al., 1997, Ott et al., 1999, Yaffe et al., 2004, Yoshitake et al., 1995). Moreover, insulin signaling is altered in post-mortem brain tissue from patients with Alzheimer's disease (AD) (Bomfim et al., 2012, Jolivalt et al., 2010, Liu et al., 2011, Moloney et al., 2010, Steen et al., 2005), and intranasal treatment with insulin has been shown to improve cognitive function in patients with aging-related mild cognitive impairment and mild-to-moderate AD (Benedict et al., 2007, Benedict et al., 2004, Craft et al., 2012, Krug et al., 2010). Thus, alterations in insulin signaling are likely to contribute to both peripheral metabolic changes and the cognitive decline that can accompany metabolic dysfunction. Indeed, several studies demonstrate that insulin and many of its downstream targets can affect neuronal activity in a manner that favors synaptic plasticity and improves cognitive performance in non-pathological conditions (Das et al., 2005, Grillo et al., 2015, Zhao et al., 1999).
These observations lead to several relevant and important questions. For instance, is there a correlation between the time course of altered peripheral metabolic phenotype, impaired CNS insulin signaling, and cognitive decline? If insulin signaling is impaired prior to cognitive decline, it may play a potential role in pathogenesis and cognitive dysfunction; on the other hand, if the two phenomena occur concomitantly, altered insulin signaling could simply be a consequence of disease progression. What underlies the change in CNS insulin signaling? Factors that could contribute to impaired CNS insulin signaling include a decrease in brain insulin levels (e.g., due to decreased peripheral production or altered capacity for insulin to cross the blood brain barrier) or a change in CNS insulin receptor (IR) sensitivity (e.g., IR desensitization due to elevated insulin levels). Could impaired peripheral insulin signaling or responsivenes be a reliable biomarker for detecting individuals susceptible to cognitive decline and dementia? Further, can pharmacological or experimental manipulations known to improve peripheral insulin signaling (e.g. insulin sensitizers or exercise) improve cognitive function in subjects with cognitive decline/dementia? Taken together, these questions are extremely significant given epidemiological data reporting an alarming increase in the incidence and prevalence of metabolic disorders worldwide (O'Neill and O'Driscoll, 2015).
While the scientific community is far from understanding the complex interaction between metabolic alterations, altered insulin signaling and cognitive decline, on-going animal model and clinical/epidemiological studies are beginning to provide insights into this relationship. In this article we briefly review the basic mechanisms of insulin signaling in the periphery and CNS and then discuss data demonstrating: 1) a role for insulin in cognitive function; 2) a relationship between insulin and human AD; 3) peripheral metabolic alterations in mouse models of AD and how these changes could potentially lead to impaired CNS insulin signaling; and 4) potential ways to target insulin signaling that could improve cognitive function in AD. Understanding how and when peripheral metabolic alterations and impaired CNS insulin signaling occur during AD pathogenesis could improve the identification of individuals who are susceptible for developing AD, and could thus allow for earlier and possibly more effective intervention. Further, understanding this complex relationship could also help in the development of novel metabolic-based therapies or pharmacological therapeutics for AD and other cognitive disorders.
Section snippets
Insulin signaling
Insulin plays a variety of roles in the periphery, most notably in the regulation of tissue metabolism by controlling cellular glucose uptake. In contrast, the brain was previously considered insulin insensitive. However, it is now known that insulin does play several roles within the CNS at the cellular or network levels, including the regulation of neuronal survival, feeding behavior, and cognition (Kleinridders et al., 2014). IRs are differentially expressed throughout the CNS, with greatest
The role of insulin in cognitive function
Ample data suggest that insulin can play a role in normal cognitive function, although exactly how it does so is still poorly understood. First, IRs are found in the CNS in regions involved with learning and memory, including the hippocampus and cerebral cortex (Biessels and Reagan, 2015). Second, exogenous treatment with insulin can improve memory in humans and animals. Peripheral administration of insulin under euglycemic conditions increases cognitive function as assessed by verbal memory
Alzheimer's disease and altered insulin signaling
AD is a neurodegenerative condition characterized by profound memory loss, the formation of β-amyloid–containing plaques and neurofibrillary tangles consisting of hyperphosphorylated tau (the classical histological hallmarks of AD) and localized CNS hypometabolism. Despite tremendous advancements in our understanding of AD neuropathology, there are no therapeutic strategies that consistently relieve cognitive symptoms or prevent, cure or slow its progression. AD is currently the 6th leading
Mouse models of AD and peripheral insulin resistance
Before proceeding, important caveats regarding AD animal model studies need to be noted. First, rodents do not develop AD. To create animal models to study AD, scientists have introduced mutated genes associated with AD pathology into the murine genome (e.g. APP, presensilin-1 and tau). This transgenic approach has led to a plethora of available models (over 150 are listed on the Jackson Laboratory web site: www.jax.org). Noteworthy among these are the Tg2576 model (APPswe, APP Swedish
Altered CNS insulin signaling
Altered peripheral glucose regulation and insulin levels/sensitivity could affect AD pathogenesis and cognitive decline through a variety of mechanisms. In general, CNS insulin is believed to be primarily derived from the periphery and relies on an active transport mechanism to cross the BBB (Banks, 2004). This transporter appears to be saturated during euglycemic conditions, but can be affected by a variety of factors including diet, plasma glucose levels, diabetes, and obesity (Banks, 2004).
Improving insulin sensitivity decreases AD-like pathology
Thus far we have presented data demonstrating that impaired peripheral metabolism is correlated with compromised CNS insulin signaling, and have argued that this can contribute to cognitive decline and pathogenesis in AD. If impaired insulin levels/sensitivity can contribute to AD, can the converse be true? Specifically, can improving CNS insulin signaling ameliorate AD-related pathology and cognitive decline? Several studies suggest an affirmative answer. Specifically, studies have shown that:
Conclusion
In conclusion, epidemiological data reveal that metabolic disease is associated with an increased risk of developing dementia, in particular AD. Further, clinical studies suggest that either hyper- or hypoinsulinemia is associated with an increased risk for developing AD and that treatments known to improve/enhance insulin signaling can improve cognitive function in both normal subjects and AD patients. The mechanisms linking insulin to cognitive function remain to be completely understood.
References (218)
- et al.
Rescue of impaired late–phase long-term depression in a tau transgenic mouse model
Neurobiol. Aging
(2015) - et al.
Therapeutic role of low-carbohydrate ketogenic diet in diabetes
Nutrition
(2009) The source of cerebral insulin
Eur. J. Pharmacol.
(2004)- et al.
Intranasal insulin improves memory in humans
Psychoneuroendocrinology
(2004) - et al.
Oxidative stress and antioxidant defense
World Allergy Organ. J.
(2012) - et al.
Short and long sleep are positively associated with obesity, diabetes, hypertension, and cardiovascular disease among adults in the United States
Soc. Sci. Med.
(2010) - et al.
Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease
J. Biol. Chem.
(2007) - et al.
Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease
Sleep Med. Rev.
(2017) - et al.
Electrophysiological and behavioral phenotype of insulin receptor defective mice
Physiol. Behav.
(2005) - et al.
How does brain insulin resistance develop in Alzheimer's disease?
Alzheimer's Dementia
(2014)