Alzheimer’s Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence

Abstract

The amyloid-b (Ab) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Ab burden in the brain have not slowed the cognitive decline, and in some instances have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Ab is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Ab as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the Ab precursor protein (AbPP) and resultant fibrillary aggregates of Ab. Evidence from in vitro and in vivo studies demonstrates that Ab oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Ab confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Ab may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Ab. Perhaps progress towards a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.

Alterations in brain TREM2 and Amyloid‐β levels are associated with neurocognitive impairment in HIV‐infected persons on antiretroviral therapy

“…The differences in levels of Ab between Hispanics and non-Hispanics reported here may stem from differences in the initial responses to HIV infection. Studies have long suggested that Ab shows antimicrobial properties that may be elicited upon viral infection (Gosztyla et al 2018), and this could explain why HIV induces Ab production. Future studies using brain samples from age-matched, healthy, HIVcontrols would be helpful in determining differential responses to HIV with regard to Ab expression in the brain.…”

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

“…Both βand γ-secretases, like the majority of proteases, have multiple physiological substrates. Furthermore, the Aβ peptide itself may have a variety of physiological roles, including by acting as a putative transcription factor, haemostatic agent, ion channel regulator, neurotrophic agent, or an antimicrobial peptide (Gosztyla, Brothers, & Robinson, 2018;Hardy, 2007;Maloney & Lahiri, 2011;Pearson & Peers, 2006;Yankner, Duffy, & Kirschner, 1990). Endogenous Aβ may even be necessary for synaptic plasticity (Puzzo et al, 2011), and complete elimination of Aβ production in primary neurons in culture can result in cell death (Plant, Boyle, Smith, Peers, & Pearson, 2003).…”

Phf15 - a novel transcriptional repressor regulating inflammation in a mouse microglial cell line

“…APP is the precursor molecule whose proteolysis forms Aβ and formation of Aβ plaques has long been thought of as the driving force behind Alzheimer's disease [67] . Aβ has more recently been found to have antimicrobial properties [68] , conferring increased resistance against infection from both bacteria and viruses [69] . App is among the significantly upregulated genes under basal conditions in our Phf15 KO cells (log 2 -fold change = 1.492 and P adj < 0.0001; see Figure 5A).…”