Amyloidogenic Amylin: Linking Type 2 Diabetes and Alzheimers Disease in Humans and Non-Humans Primates.

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Age-related forms of dementia, in particular Alzheimers disease (AD), and type 2 diabetes mellitus (T2DM) are amongst the most prevalent, disabling, and costly conditions in industrialized countries. Epidemiologic and molecular evidence acquired over the past decades identify overlapping pathological mechanisms between these conditions. Persons with AD display a progressive cognitive decline marked by the appearance of several neuropathological hallmarks including A deposition, neurofibrillary tangle formation, vascular and metabolic disturbance, and synaptic loss (1). Depending on its clinical course and disease stage, persons with T2DM have altered glycemic regulation and hyperglycemia, insulin resistance, inappropriate insulin secretion, and progressive loss of -cells. Furthermore, diabetics often display decreased mental flexibility, impaired cognitive function, cortical atrophy, and neuronal loss (2). The fact that persons with type 1 diabetes show the same mental decline, suggests that diabetes itself and not common comorbidities like age, weight, or high blood pressure, is the culprit of the cognitive dissonance and a potential link to sporadic AD. Most of the research conducted so far to define such a causative link has focused on insulin resistance and glucose impairment. While these factors undoubtedly contribute to disease progression, brain glucose metabolism is insensitive to insulin (3), and clinical trials based on insulin and/or insulin mimetic administration have been ineffective, implying other molecules/pathways are most likely involved. A common feature of AD and T2DM is that they are both amyloidogenic diseases. In AD A, the toxic peptide cleaved from the amyloid precursor protein (APP), accumulates and aggregates in hippocampal and cortical areas as well as the neurovasculature. Similarly, more than 92% of T2DM patients display amyloid deposits of islet amyloid polypeptide (IAPP/ amylin) in pancreatic islet cells and other organs like kidney, heart, vasculature, and the central nervous system (CNS). Amylin is a 37 aa peptide, co-stored and co-secreted with insulin at a ratio between 1:10-100 in pancreatic cells. It regulates satiety, food intake, and gastric emptying thus reducing blood glucose levels and body weight (4). In the pancreas amylin also regulates glucose-induced insulin secretion and the proliferation of cells (4). Like human A, human amylin shares the propensity to self-aggregate and form insoluble plaques which play a key role in cell apoptosis and T2DM dysfunction. Recently, it was shown that in addition to T2DM patients, amylin oligomers and plaque-like accumulations occur in the CNS vasculature and parenchyma of AD patients who were not diabetic not only those with T2DM but also those with AD in the absence of diabetes (5). These plaques were both independent as well as co-localized with A (5). In vitro studies have shown remarkable similarities between A and amylin cytotoxic mechanisms including membrane disruption, reactive oxygen species generation, mitochondrial, endoplasmic reticulum and proteolysis impairments, induction of apoptosis and inflammation (4,6). Furthermore, in vitro and in vivo experiments show that human amylin enhances A oligomerization (7) leading to a possible cross-seeding mechanistical link between AD and T2DM. The few epidemiological studies conducted so far to link circulating amylin levels and AD have failed to provide clear answers, and both higher and lower levels of have been found associated with higher incidence of AD (8). A possible explanation for these discrepancies is that the studies were mostly cross-sectional and amylin levels are likely to follow an early hyper- and late hypo- trajectory, similar to insulin, as the pathological process progresses. Given amylin may be an important player acting at the interface between metabolic and neurodegenerative disorders, with this proposal we wish to advance our understanding of their temporal relationships by: 1) characterizing longitudinal age-related changes of amylin levels in non-human primates from the NIA caloric restriction longitudinal study; 2) characterizing amylin trajectories in participants of the Baltimore Longitudinal Study of Aging with respect to their cognitive health and diabetic status; 3) testing possible amylin-based interventions on cognitive impairment progression. References 1-Busche MA, Hyman BT. Synergy between amyloid- and tau in Alzheimer's disease. Nat Neurosci. 2020 Oct;23(10):1183-1193. 2-Long JM, Holtzman DM. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell. 2019 Oct 3;179(2):312-339. 3-Camandola S, Mattson MP. Brain metabolism in health, aging, and neurodegeneration. EMBO J. 2017 Jun 1;36(11):1474-1492. 4-Kiriyama Y, Nochi H. Role and Cytotoxicity of Amylin and Protection of Pancreatic Islet -Cells from Amylin Cytotoxicity. Cells. 2018 Aug 6;7(8):95. 5-Jackson K, Barisone GA, Diaz E, Jin LW, DeCarli C, Despa F. Amylin deposition in the brain: A second amyloid in Alzheimer disease? Ann Neurol 2013;74:517526. 6-Press M, Jung T, Knig J, Grune T, Hhn A. Protein aggregates and proteostasis in aging: Amylin and -cell function. Mech Ageing Dev. 2019 Jan;177:46-54. 7- Zhang Y, Tang Y, Zhang D, Liu Y, He J, Chang Y, Zheng J, Amyloid cross-seeding between A and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes, Chinese Journal of Chemical Engineering, 2021;30: 225-235. 8- Mietlicki-Baase EG. Amylin in Alzheimer's disease: Pathological peptide or potential treatment? Neuropharmacology. 2018 Jul 1;136(Pt B):287-297.