Herpes Simplex Virus, Alzheimer’s Disease and a Possible Role for Rab GTPases

Abstract

Herpes simplex virus (HSV) is a common pathogen, infecting 85% of adults in the United States. After reaching the nucleus of the long-lived neuron, HSV may enter latency to persist throughout the life span. Re-activation of latent herpesviruses is associated with progressive cognitive impairment and Alzheimer’s disease (AD). As an enveloped DNA virus, HSV exploits cellular membrane systems for its life cycle, and thereby comes in contact with the Rab family of GTPases, master regulators of intracellular membrane dynamics. Knock-down and overexpression of specific Rabs reduce HSV production. Disheveled membrane compartments could lead to AD because membrane sorting and trafficking are crucial for synaptic vesicle formation, neuronal survival signaling and Abeta production. Amyloid precursor protein (APP), a transmembrane glycoprotein, is the parent of Abeta, the major component of senile plaques in AD. Up-regulation of APP expression due to HSV is significant since excess APP interferes with Rab5 endocytic trafficking in neurons. Here, we show that purified PC12-cell endosomes transport both anterograde and retrograde when injected into the squid giant axon at rates similar to isolated HSV. Intracellular HSV co-fractionates with these endosomes, contains APP, Rab5 and TrkA, and displays a second membrane. HSV infected PC12 cells up-regulate APP expression. Whether interference with Rabs has a specific effect on HSV or indirectly affects membrane compartment dynamics co-opted by virus needs further study. Ultimately Rabs, their effectors or their membrane-binding partners may serve as handles to reduce the impact of viral re-activation on cognitive function, or even as more general-purpose anti-microbial therapies.

Decoupling the Effects of the Amyloid Precursor Protein From Amyloid-β Plaques on Axonal Transport Dynamics in the Living Brain

“…Hence not only would the APP-containing vesicles lose transport capability, but other organelles would have to compete with the cytoplasmic fragment to acquire motors. We have shown that soluble peptides derived from the cytoplasmic domain of APP when injected into the squid axon inhibit transport (Satpute-Krishnan et al, 2006; Bearer and Wu, 2019) through binding to kinesin (Seamster et al, 2012). Primary hippocampal cultures or slices from the mice used in this study could be implemented to tease apart the consequences of APP SwInd expression and plaque on transport of specific cargoes.…”

Modulation of Endosome Function, Vesicle Trafficking and Autophagy by Human Herpesviruses

“…This endocytosis step is at least partly mediated by Rab GTPases, such as RAB5A and RAB11, which enable the plasma membranes with viral glycoproteins entering the cell to form endocytic tubular membranes and provide viral capsids with an envelope, as seen in the case of HSV-1 [ 178 ]. Regarding anterograde and retrograde endosomal transport of viral particles in neurons, PC12 cells have been described to have viral capsids co-localizing with the trafficking regulator RAB5A, as well as the nerve growth factor NTRK1 (TrkA), which caused a higher expression of the amyloid precursor protein (APP) and altogether could account for the negative implications of some herpesviruses, such as HSV-1 in Alzheimer’s disease [ 179 ]. Interestingly, HSV-1 has been shown to induce the fragmentation of the Golgi network upon lytic infection in some cell types, such as Vero and HEp-2 cells [ 180 ].…”

Molecular Level Insight Into the Benefit of Myricetin and Dihydromyricetin Uptake in Patients With Alzheimer’s Diseases

“…Bacteria and viruses also can induce AD, with both Porphyromonas gingivalis and Herpes simplex virus (HSV) having confirmed links with AD initiation and progression (Bearer and Wu, 2019;Dominy et al, 2019). Gingipains, produced by Porphyromonas gingivalis, is a toxic protease related to the phosphorylation of tau peptide and the ubiquitin pathology which can also increase the level of Aβ 42 in the brain (Bearer and Wu, 2019;Dominy et al, 2019). According to the results reported by Grenier et al,62.5 to 125 µg/ml of MYR had good inhibitory effect on Porphyromonas gingivalis, and this effect may be related to MYR's ability to chelate iron ions (Grenier et al, 2015).…”

“…Furthermore, physiological function disorders, such as oxidative stress, inflammation (Meraz-Ríos et al, 2013), abnormal autophagy and the damage of insulin signaling pathway (Zhang and Hölscher, 2020) were also found to cause serious damage to the brain and can lead to the manifestation of AD (Butterfield and Halliwell, 2019). Other factors are also reported as a driving force in the genesis and development of AD, such as the long-term infections of bacteria and viruses (Bearer and Wu, 2019;Dominy et al, 2019), and the dyshomeostasis of intestinal flora (Friedland, 2015).…”