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

与年龄相关的痴呆症，特别是阿尔茨海默病（AD）和2型糖尿病（T2DM）是工业化国家中最普遍、致残和最昂贵的疾病。过去几十年来获得的流行病学和分子证据确定了这些疾病之间重叠的病理机制。阿尔茨海默病患者表现出进行性认知能力下降，表现为几种神经病理学特征，包括a沉积、神经原纤维缠结形成、血管和代谢紊乱以及突触丧失(1)。根据其临床病程和疾病分期，T2DM患者有血糖调节和高血糖改变、胰岛素抵抗、胰岛素分泌不当和细胞进行性损失。此外，糖尿病患者通常表现为精神灵活性下降、认知功能受损、皮质萎缩和神经元丧失(2)。事实上，1型糖尿病患者表现出同样的智力下降，这表明糖尿病本身，而不是常见的合并症，如年龄、体重或高血压，是认知失调的罪魁祸首，也是零星AD的潜在联系。迄今为止，为确定这种因果关系而进行的大多数研究都集中在胰岛素抵抗和葡萄糖损害上。虽然这些因素无疑有助于疾病的进展，但脑葡萄糖代谢对胰岛素不敏感(3)，基于胰岛素和/或胰岛素模拟给药的临床试验无效，这意味着其他分子/途径最有可能参与其中。

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.