Regular articleNeuroprotective effects of the amylin analogue pramlintide on Alzheimer's disease pathogenesis and cognition
Introduction
A growing body of evidence demonstrates an association between metabolic abnormalities and Alzheimer's disease (AD). Epidemiologic studies have demonstrated that patients with type 2 diabetes are at significantly increased risk of developing AD (Arvanitakis et al., 2004, Xu et al., 2004). This association is further supported by serum studies that demonstrate altered levels of a number of metabolic hormones in patients with AD, including insulin, (Craft et al., 1998, Meneilly and Hill, 1993) cortisol, (Lupien et al., 1994), and leptin (Lieb et al., 2009). Moreover, neuropathologic studies demonstrate altered insulin signaling in AD brains consistent with insulin resistance (De la Monte and Wands, 2008, Rivera et al., 2005, Steen et al., 2005). A more central role of insulin signaling in AD is suggested by recent clinical studies that demonstrate an improvement in cognitive function in patients with AD following chronic administration of insulin (Craft et al., 2012). Two other metabolic hormones that activate insulin-related signaling pathways, leptin, and glucagon-like peptide 1 have also been shown to improve memory in vivo (Greco et al, 2010, McClean et al., 2011, Tezapsidis et al., 2009). Therefore, restoring insulin signaling in the brain with insulin or related metabolic hormones might provide a therapeutic benefit to patients with AD.
Amylin is a peptide hormone that is co-secreted with insulin from beta cells in the pancreas (Mitsukawa et al., 1990). Known effects of amylin include inhibiting glucagon (Gedulin et al., 1997), delaying gastric emptying (Young et al., 1995), and inducing satiety (Morley and Flood, 1991). Interestingly, human amylin has aggregative properties and is toxic in vitro due to its tendency to form amyloid fibrils (May et al., 1993). Indeed, amylin oligomers and plaques were recently reported in temporal lobe gray matter and vasculature in diabetic and nondiabetic patients with AD at autopsy, and these were independent of amyloid-β plaques (Jackson et al., 2013). However, rat and mouse amylin, which differ from the human form by 6 substitutions, and the synthetic analog pramlintide (Symlin), are nontoxic forms of amylin that do not aggregate (May et al., 1993, Nonoyama et al., 2008) and activate many of the metabolic pathways in the central nervous system (CNS) that are thought to be beneficial for memory, weight loss, mood, and other central functions. To this end, the synthetic amylin analog pramlintide causes clinical weight loss and is an approved adjunct to insulin to improve glycemic control in diabetic patients (Hollander et al., 2003, Smith et al., 2008).
The blood–brain barrier is permeable to amylin (Banks et al., 1995) and brain uptake of amylin in mice is almost 3 times greater than brain uptake of insulin (Banks and Kastin, 1998). Amylin receptors are distributed widely throughout the CNS, with the highest density of amylin binding in the area postrema, nucleus of the solitary tract, parabrachial nucleus, amygdala, hypothalamus, nucleus accumbens, and dorsal raphe (Sexton et al., 1994). Amylin also has anxiolytic and antidepressant-like (Laugero et al., 2010, Roth et al., 2009) effects and analgesic properties, (Huang et al., 2010) although the mechanism underlying these effects is not fully understood. In peripheral tissue and in the CNS, amylin interacts with the insulin signaling cascade and activates several downstream targets of insulin, including signal transducer and activator of transcription 3, AMP-activated protein kinase, and Akt, (Moon et al., 2011) cascades involved in cellular metabolism and survival (Dudek et al., 1997, Hirano et al., 2000, Mihaylova and Shaw, 2011). In addition to the insulin-signaling pathway, amylin is also a known modulator of the ERK/MAP Kinase pathway (Moon et al., 2011, Potes et al., 2012), a cascade that is thought to underlie amylin's effects on satiety (Potes et al., 2012) and that has been implicated in synaptic plasticity and memory consolidation in the hippocampus (English and Swede, 1997, Schafe et al., 2000).
Given amylin's multiple metabolic targets in the insulin signaling pathway of relevance to neuroplasticity and its newly recognized accumulation in the AD brain, we investigated how levels of circulating amylin might relate to AD diagnosis and sought to better understand the mechanisms by which this emerging relationship might occur. We first studied the association between plasma human amylin levels and AD in a large cohort of subjects with AD, mild cognitive impairment or normal cognition. To determine the direct effects of amylin on cognition and AD pathogenesis, we studied the effects of the amylin analog pramlintide on memory in the senescence-accelerated prone (SAMP8) mouse, a rodent model of accelerated senescence that is an useful model of sporadic AD (Morley et al., 2012a, Morley et al., 2012b, Pallas et al., 2008). We investigated signaling changes in vitro to verify receptor functionality and in vivo to determine potential mechanisms of relevance to cognitive improvement.
Section snippets
Human amylin plasma analysis
All subjects were community-based volunteers who were individually recruited to participate in plasma donation and cognitive evaluation at the University of Pennsylvania's Alzheimer's Disease Center. Verbal informed consent was obtained from all study participants at the time of enrollment. Subjects were eligible to participate if they were aged above 50 years and in generally good health. Subjects underwent cognitive and neurologic examinations by experts in the evaluation of neurodegenerative
Circulating plasma amylin is reduced in human subjects with MCI and AD
Circulating plasma amylin levels were measured in 206 subjects with AD, 64 subjects with MCI, and 111 subjects with no cognitive impairment. Demographic and clinical characteristics of the participant groups are displayed in Table 1. The average plasma amylin for all patients in our study was 0.77 (standard deviation = 0.69). We assessed possible confounders but found no statistically significant relationships between plasma amylin concentration and age (F[1,379] = 0.021; p = 0.88), sex (F
Discussion
Our data demonstrate, for the first time, that there is a significant association between low plasma amylin levels and MCI or AD in a sample of older adults. This association is surprising because amylin levels are positively associated with a number of classic risk factors for AD including obesity, insulin resistance, and diabetes in middle aged adults (Hou et al., 2011, Reinehr et al., 2007). In our sample, amylin was significantly associated with another classic risk factor of AD, the
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgements
Funding for this research was provided by the Alzheimer's Association (NIRG-07-59514, IIRG-12–247219). The authors thank Dr Mark A Smith, who provided guidance and insight to this work, and who sadly passed away during the execution of this project.
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