INTRODUCTION:Emerging evidence has connected Alzheimer's disease (AD) to systemic inflammation, intestinal abnormalities, and altered gut microbiota, highlighting the significance of the gut-brain axis. Here, we investigated the impact of acute experimental colitis (acute colitis) on AD pathology. METHODS:Acute colitis was induced in 2-month-old 5xFAD mice using dextran sodium sulfate (DSS) to assess the effects of intestinal inflammation on the microbiome, systemic inflammation, neuroinflammation, and beta-amyloid deposition. RESULTS:Induction of acute colitis in 5xFAD mice led to microbial dysbiosis and systemic inflammation. As a result, monocyte infiltration was observed in the brain accompanied by reduced cerebral beta-amyloid deposition and increased beta-amyloid efflux into the bloodstream. DISCUSSION:Increased infiltration of monocytes and elevated beta-amyloid release into the bloodstream could both be responsible for the reduced beta-amyloid deposition in 5xFAD mice following acute colitis. These results further highlight an important connection between gut-induced peripheral inflammation and the progression of AD. HIGHLIGHTS:Microbial dysbiosis occurs as a result of acute colitis in 5xFAD mice. Acute colitis in 5xFAD mice affects beta-amyloid deposition. Increased IL-2 and IL-6 cytokine levels in the hippocampus of 5xFAD colitis mice. Colitis in 5xFAD mice increases serum proinflammatory cytokine levels and endotoxins. Acute colitis in 5xFAD mice increases monocyte infiltration and serum beta-amyloid.

INTRODUCTION:Our previous studies demonstrated the antimicrobial properties of amyloid beta (Aβ) of Alzheimer's disease (AD) against clinically relevant bacteria, yeast, and viruses. In this study, we investigate the antimicrobial function of the 37-amino acid amylin of type 2 diabetes (T2D), expanding on its potential involvement in AD. METHODS:We used in vitro assays, including human three-dimensional neuronal cell culture models, to test microbicidal, microbiostatic, and synergistic antimicrobial interactions between amylin and Aβ against microbes. RESULTS:Our results confirm that amylin is a broad-spectrum antimicrobial peptide that exhibits both microbicidal and microbiostatic mechanisms. We also identified a synergistic antimicrobial effect between amylin and Aβ in inhibiting Salmonella Typhimurium and Staphylococcus aureus. DISCUSSION:The findings show that amylin is an antimicrobial peptide and functions synergistically with Aβ against bacterial pathogens. Increased amylin secretion after bacterial infection suggests a broader biological role for amylin beyond its involvement in T2D. HIGHLIGHTS:Amylin is a potent antimicrobial peptide, eliminating ≥99.9% bacteria at low doses. Amylin efficiently traps and neutralizes microbes via a fibril-driven mechanism. Amylin protects human cells and Caenorhabditis elegans from Salmonella or Candida infection. Synthetic amylin and amyloid beta (Aβ) together amplify antibacterial response against bacteria. Synergy between cell-derived amylin and Aβ drives dynamic antimicrobial activity against neural infection.

Tau is a microtubule-associated cytoskeletal protein, which, when hyperphosphorylated and aggregated, can result in a myriad of different tauopathies, including Alzheimer's disease (AD). We previously showed that the principal component of senile plaques, amyloid beta (Aβ), is an antimicrobial peptide capable of binding and entrapping microbial pathogens. Here we show that tau is hyperphosphorylated in neurons in response to viral infection and can neutralize herpes simplex virus 1 (HSV-1) infectivity by directly binding to viral capsids. Our data suggest that the 'pathogenic' characteristics of tau hyperphosphorylation, microtubule destabilization and aggregation are part of an antiviral response, in which tau serves as a host defense protein in the innate immune system of the brain. The combined antimicrobial activities of Aβ and phosphorylated tau resulting in Aβ plaques and neurofibrillary tangles, along with neuroinflammation, suggest that AD neuropathology may have evolved as an orchestrated innate immune host defense response to microbial infection in the brain.

Amyloid-ß (Aß) accumulation in brain is an early hallmark of Alzheimer’s disease (AD). We discovered Aß deposition, ß-amyloidopathy, and colocalizing supranuclear cataracts (SNC) in lenses from people with AD (Goldstein LE et al., Lancet, 2003) and Down syndrome (DS; Moncaster JA et al., PLoS One, 2010), but not other neurodegenerative diseases or normal aging. These findings spurred development of an investigational drug-device lens Aß eye scanner (Sapphire II, Cognoptix) that combines an Aß-binding fluorescent ligand (Aftobetin) and specialized laser scanning ophthalmoscope for noninvasive measurement of lens Aß (FDA Breakthrough Device, 2021). Early clinical results indicate that lens Aß is an ideal biomarker for early AD detection. Here, we investigated Aß accumulation and amyloidopathy in lens and brain. Tg2576 transgenic (Tg+) mice express Swedish mutant human amyloid precursor protein (hAPP-Swe), human Aß (hAß), ß-amyloidopathy, and cognitive deficits (Hsiao et al., Science, 1996). Non-transgenic (Tg–) littermates were used as controls. Lenses were examined by ex vivo lens stereomicroscopy. Brains and lenses were analyzed by Aß immunohistochemistry, amyloid histopathology, anti-Aß immunogold electron microscopy, tryptic digest mass spectrometry, anti-hAß ELISA/immunoblotting. Quasi-elastic light scattering hAß-lens protein aggregation analysis. Tg2576 Tg+ mice, but not Tg– controls, age-dependently express hAPP, accumulate hAß, and develop hAß molecular pathology in the lens and exhibit age-dependent Aß supranuclear opacification that recapitulates lens pathology and SNC phenotype expression in human AD and DS. We detected hAß in conditioned medium from Tg+ but not Tg– lens explant cultures. hAß potently promotes mouse lens protein aggregation in vitro. These results support mechanistic (genotype-phenotype) linkage between age-dependent Aß pathology and AD-related phenotypes in lens and brain. Collectively, our findings identify Aß pathology as the shared molecular etiology of age-dependent supranuclear cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD-related Aß pathology outside the brain and support lens Aß as an optically-accessible biomarker for early detection and longitudinal monitoring of AD.

Neuropathological hallmarks of Alzheimer's disease (AD) include pathogenic accumulation of amyloid-β (Aβ) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated Aβ neuropathology begins decades before onset of cognitive symptoms and slowly progresses over the course of the disease. We previously reported discovery of Aβ deposition, β-amyloidopathy, and co-localizing supranuclear cataracts (SNC) in lenses from people with AD, but not other neurodegenerative disorders or normal aging. We confirmed AD-associated Aβ molecular pathology in the lens by immunohistopathology, amyloid histochemistry, immunoblot analysis, epitope mapping, immunogold electron microscopy, quantitative immunoassays, and tryptic digest mass spectrometry peptide sequencing. Ultrastructural analysis revealed that AD-associated Aβ deposits in AD lenses localize as electron-dense microaggregates in the cytoplasm of supranuclear (deep cortex) fiber cells. These Aβ microaggregates also contain αB-crystallin and scatter light, thus linking Aβ pathology and SNC phenotype expression in the lenses of people with AD. Subsequent research identified Aβ lens pathology as the molecular origin of the distinctive cataracts associated with Down syndrome (DS, trisomy 21), a chromosomal disorder invariantly associated with early-onset Aβ accumulation and Aβ amyloidopathy in the brain. Investigation of 1249 participants in the Framingham Eye Study found that AD-associated quantitative traits in brain and lens are co-heritable. Moreover, AD-associated lens traits preceded MRI brain traits and cognitive deficits by a decade or more and predicted future AD. A genome-wide association study of bivariate outcomes in the same subjects identified a new AD risk factor locus in the CTNND2 gene encoding δ-catenin, a protein that modulates Aβ production in brain and lens. Here we report identification of AD-related human Aβ (hAβ) lens pathology and age-dependent SNC phenotype expression in the Tg2576 transgenic mouse model of AD. Tg2576 mice express Swedish mutant human amyloid precursor protein (APP-Swe), accumulate hAβ peptides and amyloid pathology in the brain, and exhibit cognitive deficits that slowly progress with increasing age. We found that Tg2576 trangenic (Tg+) mice, but not non-transgenic (Tg–) control mice, also express human APP, accumulate hAβ peptides, and develop hAβ molecular and ultrastructural pathologies in the lens. Tg2576 Tg+ mice exhibit age-dependent Aβ supranuclear lens opacification that recapitulates lens pathology and SNC phenotype expression in human AD. In addition, we detected hAβ in conditioned medium from lens explant cultures prepared from Tg+ mice, but not Tg– control mice, a finding consistent with constitutive hAβ generation in the lens. In vitro studies showed that hAβ promoted mouse lens protein aggregation detected by quasi-elastic light scattering (QLS) spectroscopy. These results support mechanistic (genotype-phenotype) linkage between Aβ pathology and AD-related phenotypes in lens and brain. Collectively, our findings identify Aβ pathology as the shared molecular etiology of two age-dependent AD-related cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD-related Aβ pathology outside the brain and point to lens Aβ as an optically-accessible AD biomarker for early detection and longitudinal monitoring of this devastating neurodegenerative disease.

The argument is frequently made that the amyloid-β protein (Aβ) persists in the human genome because Alzheimer’s disease (AD) primarily afflicts individuals over reproductive age and, therefore, there is low selective pressure for the peptide’s elimination or modification. This argument is an important premise for AD amyloidosis models and therapeutic strategies that characterize Aβ as a functionless and intrinsically pathological protein. Here, we review if evolutionary theory and data on the genetics and biology of Aβ are consistent with low selective pressure for the peptide’s expression in senescence. Aβ is an ancient neuropeptide expressed across vertebrates. Consistent with unusually high evolutionary selection constraint, the human Aβ sequence is shared by a majority of vertebrate species and has been conserved across at least 400 million years. Unlike humans, the overwhelming majority of vertebrate species do not cease reproduction in senescence and selection pressure is maintained into old age. Hence, low selective pressure in senescence does not explain the persistence of Aβ across the vertebrate genome. The “Grandmother hypothesis” (GMH) is the prevailing model explaining the unusual extended postfertile period of humans. In the GMH, high risk associated with birthing in old age has lead to early cessation of reproduction and a shift to intergenerational care of descendants. The rechanneling of resources to grandchildren by postreproductive individuals increases reproductive success of descendants. In the GMH model, selection pressure does not end following menopause. Thus, evolutionary models and phylogenetic data are not consistent with the absence of reproductive selection pressure for Aβ among aged vertebrates, including humans. Our analysis suggests an alternative evolutionary model for the persistence of Aβ in the vertebrate genome. Aβ has recently been identified as an antimicrobial effector molecule of innate immunity. High conservation across the Chordata phylum is consistent with strong positive selection pressure driving human Aβ’s remarkable evolutionary longevity. Ancient origins and widespread conservation suggest the human Aβ sequence is highly optimized for its immune role. We detail our analysis and discuss how the emerging “Antimicrobial Protection Hypothesis” of AD may provide insights into possible evolutionary roles for Aβ in infection, aging, and disease etiology.

Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.

•Amyloid-β oligomerization is not intrinsically pathological.•Amyloidosis emerges as an innate immune pathway.•Pathogens can see β-amyloid deposition.•Antimicrobial protection hypothesis of AD describes this emerging model.•The new model provides a rational framework for understanding AD amyloidosis.

We explore here a novel model for amyloidogenesis in Alzheimer's disease (AD). This new perspective on AD amyloidosis seeks to provide a rational framework for incorporating recent and seemingly independent findings on the antimicrobial role of β-amyloid and emerging experimental, genetic, and epidemiological data, suggesting innate immune-mediated inflammation propagates AD neurodegeneration. AD pathology is characterized by cerebral deposition of amyloid-β protein (Aβ) as β-amyloid. Genetic studies have confirmed the key role of Aβ in AD, revealing that mutation-mediated shifts in the peptides generation lead to early onset familial Alzheimer's disease. However, Aβ generation appears normal for the majority of AD patients, who lack early onset familial Alzheimer's disease mutations. In prevailing models of nonfamilial AD, individual genetics and age-associated changes in brain milieu promote an intrinsically abnormal propensity of Aβ for self-association. However, emerging findings are increasingly inconsistent with characterization of Aβ oligomerization as a nonphysiological and exclusively pathological activity. Recent studies suggest Aβ is an ancient, highly conserved effector molecule of innate immunity. Moreover, Aβ oligomerization and β-amyloid generation appear to be important innate immune pathways that mediate pathogen entrapment and protect against infection. Recent findings on inflammation-mediated neurodegeneration and the role of Aβ in immunity have led to emergence of the “Antimicrobial Protection Hypothesis” of AD. In this model, β-amyloid deposition is an early innate immune response to genuine, or mistakenly perceived, immunochallenge. Aβ first entraps and neutralizes invading pathogens in β-amyloid. Aβ fibrillization drives neuroinflammatory pathways that help fight the infection and clear β-amyloid/pathogen deposits. In AD, chronic activation of this pathway leads to sustained inflammation and neurodegeneration. Mounting data link elevated brain microbe levels with AD. The Antimicrobial Protection Hypothesis reveals how increased brain microbial burden may directly exacerbate β-amyloid deposition, inflammation, and AD progression. In the antimicrobial protection model, the modality of Aβ's pathophysiology is shifted from abnormal stochastic behavior toward dysregulated innate immune response. However, β-amyloid deposition in AD still leads to neurodegeneration. Thus, the new model extends but remains broadly consistent with the Amyloid Cascade Hypothesis and overwhelming data showing the primacy of Aβ in AD pathology.

A considerable body of data suggests the beta-amyloid peptide (Abeta) plays a key role in Alzheimer’s disease (AD) pathology. The physiological role for Abeta has been unclear. We recently showed that synthetic Abeta has potent in vitro antimicrobial activity against CNS pathogens. We have since generated in vivo evidence showing that Aβ protects against fungal and bacterial pathogens in transgenic mouse, Drosophila, C. elegans, and culture cell infection models, doubling host survival in some cases. Consistent with a protective role for Aβ in vivo, APP-null mice with low Aβ expression also show attenuated infection resistance. Oligomerization of Abeta is key for the protective antimicrobial actions of the peptide and mediates the agglutination and eventual entrapment of microbes in beta-amyloid deposits. The emergence of role for Abeta as an antimicrobial peptide (AMP) and recent identification of innate immune genes as AD risk factors has lead us to propose a new disease model we call the “Antimicrobial Protection Hypothesis” of Alzheimer’s disease. Here we present data on how Abeta activities mediate the peptides AMP actions against fungal, bacterial and viral pathogens. We describe how our new model provides a framework for understanding Abeta activities, including host cell cytotoxicity, metal binding and oxygen radical generation, carbohydrate binding, and immune modulatory activities.

The low-density lipoprotein receptor-related protein (LRP) is a large multifunctional cell surface membrane receptor capable of binding over 50 ligands.

Neurodegenerative Disease ManagementVol. 6, No. 5 CommentaryFree AccessAlzheimer's disease: the potential therapeutic role of the natural antibiotic amyloid-β peptideDeepak Kumar Vijaya Kumar, William A Eimer, Rudolph E Tanzi & Robert D MoirDeepak Kumar Vijaya Kumar Genetics & Aging Research Unit, Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Charlestown, MA 02129, USA, William A Eimer Genetics & Aging Research Unit, Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Charlestown, MA 02129, USA, Rudolph E Tanzi Genetics & Aging Research Unit, Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Charlestown, MA 02129, USA & Robert D Moir*Author for correspondence: E-mail Address: moir@helix.mgh.harvard.edu Genetics & Aging Research Unit, Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Charlestown, MA 02129, USAPublished Online:7 Sep 2016https://doi.org/10.2217/nmt-2016-0035AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: Alzheimer's diseaseamyloid-βinfectionFirst draft submitted: 1 August 2016; Accepted for publication: 11 August 2016; Published online: 7 September 2016Innate immunity is the oldest arm of host defense. Among invertebrates, innate immunity remains the primary defense against infection. Higher organisms have evolved additional adaptive immune responses but the pathways of innate immunity continue to play essential protective roles, including early recognition of infection in tissues, direct inhibition of pathogens through release of antimicrobial molecules, phagocytic removal of cellular debris and foreign materials by leukocytes, recruitment of immune cells to sites of infection through the release of cytokines, alerting adaptive immunity to potential threats through the complement cascade and antigen presentation, and providing chemical and physical barriers to infectious agents [1]. While innate immune responses are rapid and provide immediate host protection they are generic in that the same protective pathways are activated with widely differing immune challenges. The primary effector molecules of innate immunity are antimicrobial peptides (AMPs), also called host defense peptides. AMPs are small (typically <50 amino acids) amphipathic peptides and are expressed by both single and multicellular organisms [2]. Microbicidal and microbiostatic pathways are the most conspicuous and widely studied AMP activities. However, vertebrate AMPs are highly pleotropic in their actions and mediate a broad range of innate immune responses. The immunomodulatory activities of AMPs appear to be at least as important for host protection as the peptides direct antimicrobial actions. While essential for normal immunocompetence, mounting evidence suggests that AMPs also have a dark side. Overexpression or dysregulation of AMP pathways are implicated in the etiology of a range of chronic human diseases [3].We recently demonstrated that the amyloid-β peptide (Aβ) of Alzheimer's disease (AD) is a potent AMP and protects against infections in vivo [4,5]. Aβ is an ancient and highly conserved molecule in over 70% of vertebrate species [6]. The remarkable conservation across vertebrates and high antimicrobial activity in animal models [5] suggest Aβ is an important and potent natural AMP. This has important implications for the peptide's pathological actions in AD. However, an AMP function for Aβ also raises new and intriguing possibilities independent of the peptide's pathological role. Namely, could Aβ or Aβ derivatives be developed into clinically useful agents? The last decade has seen considerable effort to develop natural and synthetic AMPs as clinical agents to treat disease. Efforts have mostly focused on developing AMPs as peptide antibiotics. Over 20 clinical trials have been conducted using AMPs as either topical or systemic antibiotics [7]. Aβ or Aβ derivatives may have potential as clinical antibiotics. In addition, we believe there may also be opportunities for advancing peptide-based therapies by using Aβ as a model of AMP actions in vivo, particularly those protective activities mediated by peptide oligomerization.Oligomerization mediates at least two separate but overlapping Aβ antimicrobial pathways. The first is a classical AMP pathway and involves perturbation of microbial membranes by oligomeric Aβ species. Soluble Aβ oligomers bind microbial surface, then fibrilize disrupting membrane integrity. Membrane disruption pathways are the most widely characterized AMP microbicidal mechanism and the focus of most efforts to develop peptide antibiotics. However, microbial membrane disruption typically requires micromolar AMP concentrations. Aβ, and a majority of classical AMPs, are normally expressed at low nanomolar concentrations. At low nanomolar levels, a second Aβ pathway involving microbe agglutination and sequestration inhibits invading pathogens. In this pathway, soluble Aβ oligomers target and bind microbial surface carbohydrates. Oligomeric Aβ species possess enhanced carbohydrate-binding properties and are key for microbe targeting. Microbial cell wall binding by soluble Aβ oligomers is increased three to four orders of magnitude (log10) compared with monomeric peptide [8]. Once bound, oligomers provide a nidus and anchor for Aβ fibril propagation. Growing Aβ fibrils capture, agglutinate and finally entrap microbes in a network of β-amyloid. Agglutination generates high local Aβ concentrations within agglutinates and facilitates microbial killing by membrane perturbation pathways. Aβ oligomerization is key for the peptides targeting and inhibition of pathogens. Available data suggest that classical AMPs also generate soluble oligomeric species that mediate microbial targeting and inhibition pathways. However, therapeutic strategies aimed at developing clinically useful peptide antibiotics rarely consider the potential benefits of soluble oligomeric AMP species. Opsonization is another immune pathway with potential for increasing AMP clinical efficacy. In opsonization, surface-bound AMP oligomers mark a microbe for phagocytosis [9]. Administering combinations of specific pre-assembled oligomers may offer an effective strategy for targeting pathogens with a diverse array of protective AMP activities, including agglutination and opsonization pathways. Such oligomer preparations are likely to more closely model the highly efficient synergistic actions of endogenous AMPs in vivo.Soluble Aβ oligomers are integral to the antimicrobial activities of Aβ. Consistent with a key physiological role for multimer species, the pool of soluble Aβ in brain is overwhelmingly comprised of polydispersed polymorphic oligomers [10]. Aβ oligomers show antimicrobial activities that are broader and two to three orders of magnitude (log10) more potent than homodisperse monomeric peptide [5]. In addition to agglutination and opsonization, soluble AMP oligomers have been shown to mediate a range of activities important for host protection, including pathogen targeting [11], microbial cell membranes disruption [12], increase resistance to proteases that inactivate host immune peptides [13] and broadening the spectrum of microbes targeted by AMP families [8]. A large body of data is available on the structure, physiochemistry and activities of Aβ oligomers. It seems likely this data contain useful insights into oligomer-mediated activities of classical AMPs and may also help guide future efforts to develop specific multimer configurations that increase the efficacy of peptide antibiotics.Aβ oligomer models may prove especially helpful in overcoming the most often cited challenges to using AMPs as antibiotic drugs [7], including: first, high dose required for efficacy; second, high cost of peptide production and third, high vulnerability to environmental degradation. Aβ oligomers show robustly increased potency, specificity and stability. Enhanced antimicrobial activities for oligomers of classical AMPs would reduce the dosage required for effective antibiotic actions. Lower doses would reduce drug costs per patient. The potential to direct or broaden pathogen specificity through generation of specific oligomeric species would also expand possible applications available for single peptide products. This would help consolidate peptide synthesis processes and further reduce production costs. Finally, the high stability of Aβ multimers suggests that AMP oligomer preparations are also likely to resist environmental degradation and show enhanced shelf-lives compared with monomeric peptides. Soluble AMP oligomers may also offer an additional incentive for the pharmacological industry. Soluble oligomer preparations would be categorized as biopharmaceuticals. Biologics generated by a production process of controlled oligomerization are likely to be considerably more difficult and costly to replicate/authenticate than traditional generic drugs, which only duplicate a simple chemical structure.In addition to providing a model for peptide antibiotic development, there are potential clinical applications for Aβ itself. The in vitro antimicrobial Aβ activities match, and in some cases exceed, those of AMPs previously trialed as antibiotics [4,5]. Aβ also shows a broad activity spectrum, showing activity against fungi, bacteria and viruses. Thus, data suggest that Aβ or Aβ derivatives are feasible candidates for development as peptide antibiotics. Potential clinical uses for Aβ also extend beyond use as an antibiotic. LL-37 is an archetypal human AMP that has been our model for the antimicrobial actions of Aβ. LL-37 is currently being trialed as an anticancer drug (identifier NCT02225366 at ClinicalTrials.gov). Studies have not focused on the anticancer activities of Aβ. However, human Aβ expression in transgenic mice has been reported to inhibit the growth of tumors transplanted into the brain [14]. The cytotoxic mechanism appears specific for glioma cells. AMPs are also potent cytokines and are currently being explored as immunomodulator drugs [15]. Aβ in the CNS is proinflammatory but potently anti-inflammatory when administered in the periphery [16]. However, for over three decades Aβ has been associated with AD pathology and several potential safety concerns will need to be addressed before the peptide can be used as a drug. Most prominent is the potential for Aβ host cytotoxicity. Aβ is frequently characterized as 'highly cytotoxic'. However, among eukaryotic cells, high Aβ cytotoxicity appears limited to neurons. Moreover, neurotoxicity requires highly specific and uncommon Aβ oligomer species. Indeed, generating experimental Aβ species with consistent neurotoxic activity has proved a major challenge [17]. The overwhelming majority of monomeric and oligomeric Aβ species do not appear cytotoxic toward neurons or other eukaryotic cells. Broad cytotoxicity against eukaryotic cells requires high Aβ concentrations (>50 µM) that typically exceed levels likely to be used clinically. Indeed, many classical AMPs show broad host cytotoxicity at considerably lower concentrations than Aβ. The adage 'dose makes the poison' remains as relevant today as when first expressed over five centuries ago. At the concentrations likely to be used clinically, Aβ host cytotoxicity seems unlikely to preclude the peptides use as an antibiotic. Moreover, selectively removing or inhibiting the generation of rare problematic species in Aβ preparations seems a viable strategy should neurotoxicity prove a problem.β-amyloid deposition in host tissues is also a likely concern for systemic use of an Aβ drug. Aβ is normally expressed in blood and peripheral tissues. However, Aβ outside the brain has not been reported to lead to amyloidosis. β-amyloid deposited in the periphery may be cleared by the immune system. This model is consistent with findings for the protective actions of Aβ autoantibodies and AD immune therapies that stimulate immune-mediated clearance of β-amyloid from brain [18]. However, it remains unclear if immune-mediated clearance would be sufficiently robust to clear levels of exogenous Aβ administered as a therapeutic agent. For clinical trials, natural AMPs with high host cytotoxicity have been modified to reduce toxicity [7]. A possible strategy to limit amyloid generation in tissues may be to use modified human Aβ or nonhuman sequences. Rodent and human Aβ sequences diverge by three amino acids. Rodent Aβ generates diffuse deposits with infection that are more readily cleared than human β-amyloid plaques [19]. Use of rodent Aβ peptides may reduce potential problems associated with systemic β-amyloid accumulation.It remains to be determined if Aβ is suitable for use as a clinical antibiotic, anticancer or immunomodulator drug. However, an analysis of available data suggests that serious consideration should be given to exploring possible therapeutic applications for this ancient and highly conserved immune molecule.In summary, we believe Aβ may be useful for advancing development of peptide antibiotics. Firstly, Aβ or Aβ derivatives may themselves be candidate therapeutic agents. However, safety concerns will need to be addressed as to the potential for β-amyloid accumulation in patient peripheral tissues. Secondly, Aβ may provide a useful model for development of soluble AMP oligomers as therapeutic agents. AMP oligomers are likely to show increased potency, specificity and stability compared with the monomeric peptides used in clinical trials to date. Enhanced antimicrobial efficacy for peptide oligomers may have the additional benefit of lowering current high costs of AMP antibiotic therapies. The emerging role of innate immune pathways in AD pathology is helping change how β-amyloid deposition in brain is viewed. However, the emerging AMP identity for Aβ has also revealed the potential for new beneficial roles for a peptide long perceived only as an intractable enemy.Financial & competing interests disclosureThis work is supported by grants from NIH (5R01AI081990-02), the Cure Alzheimer's Fund and The Helmsley Charitable Trust. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Papers of special note have been highlighted as: • of interest; •• of considerable interestReferences1 Flajnik MF, Du Pasquier L. Evolution of innate and adaptive immunity: can we draw a line? 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Environmental factors may be generalizableBrain Research, Vol. 1671Introducing a new volume of Neurodegenerative Disease ManagementLaura Dormer27 January 2017 | Neurodegenerative Disease Management, Vol. 7, No. 1 Vol. 6, No. 5 Follow us on social media for the latest updates Metrics History Published online 7 September 2016 Published in print October 2016 Information© Future Medicine LtdKeywordsAlzheimer's diseaseamyloid-βinfectionFinancial & competing interests disclosureThis work is supported by grants from NIH (5R01AI081990-02), the Cure Alzheimer's Fund and The Helmsley Charitable Trust. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

The amyloid-β peptide (Aβ) is a key protein in Alzheimer’s disease (AD) pathology. We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.

With the growing aging population in Western countries, Alzheimer’s disease (AD) has become a major public health concern. No preventive measure and effective treatment for this burdensome disease is currently available. Genetic, biochemical, and neuropathological data strongly suggest that Aβ amyloidosis, which originates from the amyloidogenic processing of a metalloprotein-amyloid precursor protein (APP), is the key event in AD pathology. However, neurochemical factors that impact upon the age-dependent cerebral Aβ amyloidogenesis are not well recognized. Growing data indicate that cerebral dysregulation of biometals, environmental metal exposure, and oxidative stress contribute to AD pathology. Herein we provided further evidence that both metals (such as Cu) and H2O2 promote formation of neurotoxic Aβ oligomers. Moreover, we first demonstrated that laser capture microdissection coupled with X-ray fluorescence microscopy can be applied to determine elemental profiles (S, Fe, Cu, and Zn) in Aβ amyloid plaques. Clearly the fundamental biochemical mechanisms linking brain biometal metabolism, environmental metal exposure, and AD pathophysiology warrant further investigation. Nevertheless, the study of APP and Aβ metallobiology may identify potential targets for therapeutic intervention and/or provide diagnostic methods for AD.