HSV-1 and Alzheimer's disease: more than a hypothesis

Abstract

Among the multiple factors concurring to Alzheimer's disease (AD) pathogenesis, greater attention should be devoted to the role played by infectious agents. Growing epidemiological and experimental evidence suggests that recurrent herpes simplex virus type-1 (HSV-1) infection is a risk factor for AD although the underlying molecular and functional mechanisms have not been fully elucidated yet. Here, we review literature suggesting the involvement of HSV-1 infection in AD also briefly mentioning possible pharmacological implications of these findings.

Keywords: Alzheimer’s disease; HSV-1; amyloid-β protein; recurrent infection; γ secretase.

FIGURE 1

HSV-1 infection induces APP cleavage. (A) Our data suggest that HSV-1 binding to the heparan sulfate proteoaminoglycans (HSPGs) expressed on neuronal plasma membrane induces Ca²⁺ signals triggering APP phosphorylation at Thr668 that, in turn, increases β- and γ-secretase activity. As a result, there is an increased production of Aβ that aggregates to form oligomers of various size. The C-terminal APP fragment called AICD, created by the cleavage of γ secretase is phosphorylated at Thr668 and internalized in the nucleus where it may modulate gene transcription. (B) Western blots showing representative experiments performed with 4G8 antibody and anti pAPP^Thr668 on intracellular lysates of neuronal cells. Asterisks in the blots indicate bands that are modified by 18 h of HSV-1 infection (hours post infection, hpi) with respect to the mock-infected conditions. Double asterisk in the Western blot for 4G8 indicates the APP fragment F35, characteristic of HSV-1 infected cells. (C) Cartoon indicating the amino acid sequences targeted by the different antibodies we used for Western blot and immunofluorescence experiments: 4G8 recognizes all APP fragments containing the amino acid sequence 17–24 of Aβ, independently on its cleavage. Therefore, it reacts with APP “full-length”, and with all APP fragments that contain Aβ 17–24 sequence; pAPP^Thr668 antibody reacts with all C-terminus APP fragments containing phosphorylated Thr668, including APP full-length; anti Aβ42 C-terminus specifically reacts with the C-terminal part of Aβ42, and it does not recognize APP. Western blots in the panel B refer to previously published data (De Chiara et al., 2010).

FIGURE 2

HSV-1 infection induces intracellular accumulation of several APP fragments. Representative examples of mock and HSV-1-infected (18 hpi) rat cortical neurons immunostained for Aβ42 C-terminus (green) and HSV-1 (red; A); pAPP^Thr668/AICD^pThr668 (green) and MAP-2 (red; B). Nuclei are stained in blue with DAPI. White arrowheads in the panel A (right) indicate intracellular accumulation of Aβ42 in infected (HSV-1-positive) neurons. In the panel B (right), yellow arrowheads indicate nuclear accumulation of AICD^pThr668 in infected neurons (MAP-2-positive) whereas white arrowheads indicate staining for putative APP full-length phosphorylated at Thr668. Images in the panels A and B refer to previously published data (Piacentini et al., 2011).