APP Processing Induced by Herpes Simplex Virus Type 1 (HSV-1) Yields Several APP Fragments in Human and Rat Neuronal Cells

Abstract

Lifelong latent infections of the trigeminal ganglion by the neurotropic herpes simplex virus type 1 (HSV-1) are characterized by periodic reactivation. During these episodes, newly produced virions may also reach the central nervous system (CNS), causing productive but generally asymptomatic infections. Epidemiological and experimental findings suggest that HSV-1 might contribute to the pathogenesis of Alzheimer's disease (AD). This multifactorial neurodegenerative disorder is related to an overproduction of amyloid beta (Aβ) and other neurotoxic peptides, which occurs during amyloidogenic endoproteolytic processing of the transmembrane amyloid precursor protein (APP). The aim of our study was to identify the effects of productive HSV-1 infection on APP processing in neuronal cells. We found that infection of SH-SY5Y human neuroblastoma cells and rat cortical neurons is followed by multiple cleavages of APP, which result in the intra- and/or extra-cellular accumulation of various neurotoxic species. These include: i) APP fragments (APP-Fs) of 35 and 45 kDa (APP-F35 and APP-F45) that comprise portions of Aβ; ii) N-terminal APP-Fs that are secreted; iii) intracellular C-terminal APP-Fs; and iv) Aβ1-40 and Aβ1-42. Western blot analysis of infected-cell lysates treated with formic acid suggests that APP-F35 may be an Aβ oligomer. The multiple cleavages of APP that occur in infected cells are produced in part by known components of the amyloidogenic APP processing pathway, i.e., host-cell β-secretase, γ-secretase, and caspase-3-like enzymes. These findings demonstrate that HSV-1 infection of neuronal cells can generate multiple APP fragments with well-documented neurotoxic potentials. It is tempting to speculate that intra- and extracellular accumulation of these species in the CNS resulting from repeated HSV-1 reactivation could, in the presence of other risk factors, play a co-factorial role in the development of AD.

Intracellular Accumulation of Amyloid- (A ) Protein Plays a Major Role in A -Induced Alterations of Glutamatergic Synaptic Transmission and Plasticity

“…Freeze-dried purified A␤40, A␤42, A␤42-1, and A␤42 variant harboring oxidized methionine at position 35 (A␤42 MO ) and human amylin were purchased from AnaSpec. Protein solutions were prepared as previously described (Piacentini et al, 2008a;De Chiara et al, 2010;Maiti et al, 2011;Attar et al, 2012; according to standard procedures. Briefly, peptides were diluted to 1 mM in 1,1,1,3,3,3,-hexafluoro-2-propanol to disassemble preformed aggregates and stored as dry films at Ϫ20°C before use.…”

A protective role for herpes simplex virus type-1-specific humoral immunity in Alzheimer’s Disease

“…The presence of a possible connection between HSV-1 and AD was first suggested more than 30 years ago [8]. This suggestion was subsequently strengthened by a number of in vitro data indicating that HSV-1 infection of neuron cell lines results in the same molecular alterations that are observed in AD, including APP processing [9] and intracellular distribution [10], and τ protein phosphorylation [11]. Notably, the possible connection between HSV-1 and AD has also been reinforced over the years by a number of epidemiological results (for a very recent state-of-the art document, see: Itzhaki et al 2016 [12]).…”

How plausible is a link between HSV-1 infection and Alzheimer’s disease?

“…All these diseases can develop decades after the primary infection. Molecular evidences show that HSV-1 infection of neuronal and glial cells results in an increase of the intracellular levels of b amyloid (Ab), a decrease of the amyloid precursor protein and the phosphorylation of Tau protein, the main component of neurofibrillary tangles [8][9][10][11]: these are the same cellular events associated with the development of AD. Recent results have also demonstrated that the interaction between amyloid precursor protein and the HSV-1 capsid proteins [12] is essential to allow the migration of new viral particles inside infected cells.…”