Uncorrected Author Proof Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-190156 IOS Press 1 Diabetes Promotes Development of Alzheimer’s Disease Through Suppression of Autophagy 1 2 3 Ya Miao a,1 , Donghao Guo a,1 , Wei Li and Yuan Zhong ∗ 4 Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China 5 Handling Associate Editor: Yong Guo 6 Accepted 4 March 2019 Abstract. Recent studies suggest that diabetes predisposes patients to develop neurodegenerative Alzheimer’s disease (AD), although the underlying mechanisms have yet to be determined. Compromised autophagy of neuronal cells, which occurs in the early stages of AD, has been shown to enhance disease progression. However, autophagic regulation as a mechanism connecting diabetes and AD has not been shown before. Here, we found that streptozotocin (STZ)-induced diabetic rats exhibited poorer performance on the social recognition test, Morris water maze, and plus-maze discriminative avoidance task, compared to PBS-treated normoglycemic control rats, likely resulting from increased brain deposition of amyloid- peptide aggregates (A) and increased phosphorylation of tau protein, two pathological features of AD. Moreover, diabetes-induced AD-like behavioral and pathological changes were associated with a decrease in neuronal cell autophagy. Furthermore, compromised cell autophagy was recapitulated in vitro in neuronal cells cultured in high glucose conditions. Thus, our data suggest that hyperglycemia in diabetes may directly inhibit neuronal cell autophagy, which subsequently enhances AD-associated pathological progression. 7 8 9 10 11 12 13 14 15 16 17 Key words: Alzheimer’s disease, amyloid- peptide aggregates, autophagy, diabetes, tau 18 INTRODUCTION 19 Progressive loss of learning potential and mem- 20 ory is the central symptom of Alzheimer’s disease 21 (AD) [1], the pathology of which includes acceler- 22 ated deposition of extracellular senile plaques with 23 amyloid- peptide aggregates (A), and formation 24 of intraneuronal neurofibrillary tangles (NFTs) by 25 hyperphosphorylated tau proteins [2, 3]. Recently, the 26 occurrence of AD was found to be more pronounced 27 in patients with diabetes mellitus (DM) [4], a chronic 28 metabolic disease resulting from failed regulation of 29 systemic blood sugar [5]. 30 1 These authors contributed equally to this work. ∗ Correspondence to: Yuan Zhong, Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People’s Hos- pital, 600 Yi Shan Road, Shanghai 200233, China. Tel.: +86 2124056227; E-mail: zhongyuan zhy@163.com. DM is characterized by the eventual loss of 31 insulin-producing beta cells, hyperglycemia and the 32 vascular sequelae thereof [6]. The predisposing rela- 33 tionship between DM and AD was only recognized 34 in recent years. Sustained hyperglycemia can induce 35 mild proinflammatory signaling in the brain, which 36 impairs neuronal synapse deterioration and degen- 37 eration of neuronal cells [7, 8]. Moreover, chronic 38 hyperglycemia may influence the functionality of 39 microglia, thereby facilitating the pathological pro- 40 gression of AD [9]. However, the exact molecular 41 mechanisms that underlie the development of AD in 42 the setting of DM remain elusive. 43 Autophagy is a protective process undertaken by 44 cells in response to nutrient and oxygen deprivation 45 [10]. Failed autophagy results in progressive cell 46 death [11]. Hence, apoptosis and autophagy are 47 coupled procedures and share numerous regulatory 48 signaling pathways. During autophagy, lysosomal 49 ISSN 1387-2877/18/$35.00 © 2019 – IOS Press and the authors. All rights reserved