In 2004, Bishop and Robinson [1] hypothesised that one function of β-amyloid (Aβ) might be to protect against pathogens and now Soscia et al. present convincing experimental data for a role of Aβ as an antimicrobial peptide that may normally function in the innate immune response [2]. These results might explain why several micro-organisms lead to Aβ accumulation in cell culture and/or in mouse models. Chlamydia pneumonia and Borrelia burgdorferi spirochetes have been detected in a high proportion of Alzheimer’s disease (AD) brains [3,4], and both can cause AD-like changes [5,6]. Similarly, herpes simplex virus type 1 (HSV1), which is a risk for AD when present in the brains of APOE-ε4 carriers [7], leads to AD-like changes in cell cultures and mouse brains [8,9], and significantly, viral DNA is very specifically located in AD amyloid plaques [10] (throughout the plaque, not just on the “sticky” surface, as shown in sections that are much thinner than the average plaque diameter). Tests of Aβ’s antimicrobial action against these micro-organisms, as they are directly implicated in AD, would be of particular interest. A significant proportion of antimicrobial peptides show activity against viruses, though this is difficult to predict from sequence alone [11]. One practical difficulty of testing antiviral activity is that any apparent decline in infection due to interference with viral replication must be distinguished from effects on the mammalian cells hosting the viral infection – a particular difficulty for cytotoxic agents like Aβ, as we reported previously [9].

The findings of Soscia et al. may also impact our previously reported observations that the receptor binding region of human apolipoprotein E – the protein coded by APOE, the type 4 allele of which is a major genetic susceptibility factor for AD – has broad antibacterial and antiviral activity [12], and can be utilised to generate a family of broadly acting potent antimicrobial peptides [13]. It would be interesting to examine whether Aβ and apoE demonstrate additive and/or complimentary antimicrobial activities.

The reason why the micro-organisms cause Aβ accumulation is unknown and in the case of HSV1 it seems paradoxical, as the virus decreases the synthesis of most host cell proteins. One possible explanation for the increase in Aβ might be that it is required for the synthesis of progeny micro-organisms, and in fact Aβ fibrils enhance infection of several enveloped viruses, including HSV1 [14]. Alternatively, cells might increase Aβ as part of their defence response, with Aβ possibly acting as an antimicrobial peptide, as Soscia et al. suggest. This is supported by data showing that HIV [15], HSV2 (unpublished observations), and the bacteria mentioned above, and also chemicals (such as hydrogen peroxide [16] and mercury [17]), increase Aβ production. Aβ might initially entomb the agent (at least in the case of pathogens), as implied by Bishop and Robinson [1], thereby preventing further damage to the host, but eventually, through over-production, resulting in toxicity via oligomer formation. However, our investigations into the effect of Aβ on HSV1 revealed that it does not have antiviral activity under the conditions of our experiments, perhaps arguing against a direct defence role for Aβ against HSV1 [9]. Nonetheless in vitro tests of Aβ for antiviral or antibacterial activity might depend on its conformation or extent of aggregation, and therefore it would important to test the antiviral activity of Aβ as prepared in the Socia et al study.

Ruth F Itzhaki, Curtis B Dobson, Matthew A Wozniak

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