Uncorrected Author Proof Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-191014 IOS Press 1 Review 1 Inflammation: A Major Target for Compounds to Control Alzheimer’s Disease 2 3 Ricardo B. Maccioni * , Leonardo P. Navarrete, Andrea Gonz´ alez, Alejandra Gonz´ alez-Canacer, Leonardo Guzm´ an-Mart´ ınez and Nicole Cort´ es 4 5 Laboratory of Neuroscience and Functional Medicine, International Center for Biomedicine, Vitacura, Santiago, Chile, and Faculty of Sciences, University of Chile, ˜ Nu˜ noa, Santiago, Chile 6 7 Accepted 25 May 2020 Abstract. Several hypotheses have been postulated to explain how Alzheimer’s disease is triggered, but none of them provide a unified view of its pathogenesis. The dominant hypothesis based on build-ups of the amyloid- peptide has been around for longer than three decades; however, up to today, numerous clinical trials based on the amyloid postulates have been attempted, but all of them have failed. Clearly, the revisited tau hypothesis provides a better explanation of the clinical observations of patients, but it needs to integrate the cumulative observations on the onset of this disease. In this context, the neuroimmuno modulation theory, based on the involvement of inflammatory events in the central nervous system, accounts for all these observations. In this review we intend to emphasize the idea that neuroinflammation is a main target for the search of new therapeutic strategies to control Alzheimer’s disease. Beyond mono-targeting approaches using synthetic drugs that control only specific pathophysiological events, emerging therapeutics views based on multi targeting compounds appear to provide a new pathway for Alzheimer’s disease treatment. 8 9 10 11 12 13 14 15 16 17 Keywords: Alzheimer’s disease, astrocytes, mediators, microglial cells, neuroinflammation, proinflammatory tau pathology 18 INTRODUCTION 19 Despite the major advances in Alzheimer’s disease 20 (AD) research, there is a lack of reliable therapeu- 21 tic approaches to control this brain disease. Plaques 22 and tangles have so far been the focus of attention 23 in this progressive disorder that currently afflicts 50 24 million people all over the world [1]. Alzheimer´s 25 disease (AD) is a multi factorial disease. Plaques 26 deposits of a protein fragment called amyloid- (A), 27 look like clumps in the spaces between neurons. Tan- 28 gles, twisted fibers of tau, look like bundles of fibers 29 that build up inside cells [2]. Beyond tangles and 30 * Correspondence to: Ricardo B. Maccioni MD, PhD, Inter- national Center for Biomedicine (ICC), Vitacura 3568, D511, Vitacura, Santiago, Chile. Tel.: +56229536362; E-mail: icc@manquehue.net. plaques, cumulative evidence on the main causes of 31 this disease point to neuroinflammatory processes 32 involving alterations in the cross-talks between glial 33 cells and brain neurons. Thus, inflammation appears 34 as a major target for anti-AD compounds. Another 35 pathophysiological factor is the microbiota [3, 4]. It 36 is worth to point out that those pathogenic microor- 37 ganisms and secreted toxins from the microbiota 38 (such as bacterial amyloids and lipopolysaccharide 39 (LPS)) appear to act as proinflammatory events that 40 are involved as a main “damage signal” to favor 41 neuronal degeneration in hippocampal neurons [4]. 42 In that regard, it has been demonstrated that in 43 the APP/PSS1 tg mice the gut microbiota shifts 44 when compared to the wt counterpart at 6 months, 45 with increased presence of proteobacteria (gram 46 negative-LPS production) and Erysipelotrichaceae 47 (gram positive-inflammation related family) [5]. In 48 ISSN 1387-2877/20/$35.00 © 2020 – IOS Press and the authors. All rights reserved