International Journal of Molecular Sciences Review The Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease Umar H. Iqbal, Emma Zeng and Giulio M. Pasinetti * Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; [email protected] (U.H.I.); [email protected] (E.Z.) * Correspondence: [email protected]; Tel.: +1-212-241-7938 Received: 29 May 2020; Accepted: 10 July 2020; Published: 12 July 2020 Abstract: The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer’s disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-β peptides being limited at best, a greater understanding of the physiological role of amyloid-β peptides is needed. The development of amyloid-β plaques has been determined to occur 10–20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-β peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-β plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-β, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer’s disease. Keywords: Alzheimer’s disease; amyloid-β; antimicrobial; antiviral; antimicrobial peptide 1. Alzheimer’s Epidemiology Alzheimer’s disease (AD) is a progressive neurological disorder that accounts for the greatest number of dementia cases. As of 2019, 5.8 million people were living with AD, with its prevalence predicted to increase to 13.8 million by 2050 [1]. The vast majority of cases are concentrated in ages over 65, impacting 10% of people in this age group. In addition, the economic toll of AD on the United States economy is significant, estimated to be roughly USD 290 billion in 2019 [1]. As the number of cases is only expected to rise over the coming decades, research in this field is critical in order to understand the pathology of this disease, as well as potential therapeutics. 2. Timeline/Characterization of Alzheimer’s Disease The understanding and characterization of AD can be traced back over 100 years to Alois Alzheimer, from whom the disease takes its name. After completing an autopsy of a patient with progressive dementia, Alzheimer noticed a severe amount of cortical degeneration and an accumulation of protein deposits, specifically extraneuronal plaques and intraneural tangles [2]. By 1991, the buildup of extraneuronal amyloid-β (Aβ) plaques became the hallmark trait of the pathogenesis of Alzheimer’s disease [3], initiating the development of the amyloid cascade hypothesis [4]. In parallel to Aβ plaques formation, the accumulation of other naturally unfolded proteins is central to AD and other cerebral proteopathies [5]. The intracellular aggregation of tau proteins in the form of neurofibrillary tangles (NFTs) is also an essential trait in the pathogenesis of Alzheimer’s disease [3,6]. A recent 2020 study Int. J. Mol. Sci. 2020, 21, 4920; doi:10.3390/ijms21144920 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 20 Int. J. Mol. Sci. 2020, 21, 4920 2 of 19 Alzheimer’s disease [3,6]. A recent 2020 study found that neuroinflammation could play a role in the aggregation of tau, as DNA extracted from various bacterial species promoted tau misfolding [7]. foundWhereas that A neuroinflammationβ plaques are more could critical play to aAD role pathogen in the aggregationesis, the tau of protein tau, as DNAappears extracted to be frommore variousresponsible bacterial for subsequent species promoted cognitive tau impairment misfolding and [7]. Whereasdementia Asymptomsβ plaques as aresociated more critical with AD to AD[8]. pathogenesis,Indeed, tau hyperphosphorylation the tau protein appears and to NFT bemore levels responsible are closely forcorrelated subsequent with cognitivecognition, impairment and exhibit andpotential dementia as therapeutic symptoms targets associated for AD with treatment AD [8]. Indeed,[9]. Furthermore, tau hyperphosphorylation tau protein production and NFT has levels been areshown closely to have correlated a positive with correla cognition,tion andwith exhibit the production potential of as A therapeuticβ plaques [10], targets with for the AD formation treatment and [9]. Furthermore,lack of clearance tau proteinof Aβ plaques production also hasbeing been proposed shown to to have induce a positive tau protein correlation formation with into theproduction NFTs [11]. ofCoupling Aβ plaques this with [10], the with bi-directional the formation relationship and lack of between clearance Aβ of plaques Aβ plaques and neuroinflammation also being proposed [12] to inducewould taucement protein Aβ’s formation key role intoin driving NFTs [ 11AD]. Couplingpathology. this with the bi-directional relationship between Aβ plaques and neuroinflammation [12] would cement Aβ’s key role in driving AD pathology. 2.1. Amyloid-β Generation 2.1. Amyloid-β Generation Aβ formation begins with the breakdown of the amyloid precursor proteins (APP) embedded in the membranesAβ formation of beginscells, such with as the neurons, breakdown as a type of the 1 amyloidtransmembrane precursor glycoprotein proteins (APP) [13]. embedded Aβ peptides in theare membranesproduced through of cells, sucha two-step as neurons, cleavage as a type process, 1 transmembrane in which APP glycoprotein is metabolized [13]. Aβ intopeptides smaller are producedfragments. through In the afirst two-step step, cleavageAPP is cleaved process, by in β which-secretase APP is1 metabolizedinto a membrane-bound into smaller fragments. CTFβ fragment In the first(containing step, APP 99 is amino cleaved acids) by β and-secretase an extracellular 1 into a membrane-bound fragment sAPPβ CTF. CTFβ fragmentβ is then further (containing cleaved 99 amino by γ- acids)secretase and to an create extracellular the final fragment Aβ peptide sAPP [13–15],β. 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This insoluble is further amyloid supported fibrils thanby a Astudyβ1–40 using[18]. Thistransgenic is further mice supported that expressed by a study either using Aβ1–40 transgenic (BRI- A miceβ40) or that A expressedβ1–42 (BRI- eitherAβ42A). Aβ 1–40The (BRI-authors Aβ found40) or Athatβ1–42 the(BRI- mice A βthat42A). selectively The authors expressed found thatAβ1–40 the did mice not that develop selectively AD expressedpathology Aatβ 1–40any didage. not However, develop the AD same pathology did not at anyhold age. true However, for BRI- A theβ42A same mice, did notwhich hold had true developed for BRI- A Aββ42A deposits mice, which[19]. In had addition, developed another Aβ deposits study found [19]. In A addition,β1–42 peptides another to promote study found Aβ Aplaquesβ1–42 peptides formation, to promote and Aβ A1–40β plaquesto decrease formation, Aβ deposition and Aβ1–40 [20].to These decrease findings Aβ deposition would indicate [20]. These the findingskey role wouldAβ1–42 peptides indicate the play key in role the Apathogenesisβ1–42 peptides of playAD. in the pathogenesis of AD. FigureFigure 1.1. GenerationGeneration ofof AAββ plaques. Int. J. Mol. Sci. 2020, 21, 4920 3 of 19 2.2. Current Interventions and Limitations Even with the tremendous effort that has been put into developing potential therapies for AD over the past few decades, there has been little success in reaching an effective therapy, with no new drug being approved in over a decade. While cholinesterase inhibitors and memantine are FDA-approved drugs for AD, and do address some of its symptoms, they lack the ability to attenuate disease progression. Over the past 20 years, a majority of the therapies have been based on the amyloid cascade hypothesis, and hence have focused on depleting Aβ peptides.