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• W4234334539 abstract "The results of Satpute-Krishnan et al. (2003) introduce a welcome new approach to Alzheimer's disease (AD), relating the underlying molecular events to neuronal action and viral infection. The authors have linked the seemingly disparate worlds of amyloid and herpes viruses via the more neutral domain of the giant axon of the squid – the fons et origo, of our knowledge regarding nerve conduction/impulses. Their aim was to investigate the mechanism whereby herpes simplex virus type 1 (HSV1) in the neuronal cell body, when reactivated from its normal state of latency within the human peripheral nervous system (PNS), travels along the axon by anterograde transport to its site of entry into the host at the mucosal epithelium. The virus is shed there, probably in everybody infected with HSV1 (not, as the authors imply, just in those people – some 20–40%– who develop cold sores), and is thus transmitted in the saliva to another host. The paper suggests that the presence of HSV1 could affect the transport of amyloid precursor protein (APP), leading to its misplacement and that of its hydrolysis products, causing synaptic and neuronal dysfunction of the type seen in AD, and this could account for the pathogenic effects of the virus. The effect of HSV1 on synaptic function has not been studied, so the hypothesis of Satpute-Krishnan et al. remains to be tested. However, what is known and is highly relevant to AD is that synaptic dysfunction is closely correlated with extent of memory impairment – in marked contrast to the absence of correlation of any memory or cognitive defects with amount of amyloid plaques or of neurofibrillary tangles. Thus the study by Satpute-Krishnan et al. might indicate a cause not only of cognitive decline in AD, via aberrations in synaptic function, but also of plaque formation, the cause of which is a problem conveniently ignored, despite its importance, by those who maintain that β-amyloid deposition is the primary event in the disease. In any case, the approach of Satpute-Krishnan et al. is very probably useful in considering HSV1 transport in the human PNS – a topic relevant to the very high proportion of people (certainly in the age group of those afflicted with AD) who are infected with HSV1, in all of whom the virus remains life-long in the PNS. What happens in the central nervous system, and whether apolipoprotein E (APOE) has a role in axonal transport, is unknown, but a virus–APP association is certainly consistent with our discoveries that (a) HSV1 resides in the brain of a high proportion of elderly people (Jamieson et al., 1991); (b) it confers a high risk of AD when in APOE-ɛ4 carriers, accounting for about 60% of those we examined (Itzhaki et al., 1997; Lin et al., 1998; Dobson et al., 2003); (c) HSV1 infection of cultured human neuroblastoma cells causes an accumulation of a C-terminal 55-kDa fragment of APP (Dobson et al., 2002). Furthermore, a study by Benboudjem et al. (2003) describes another association between HSV1 and APP: a viral protein (US11) co-localizes and interacts with the cellular protein PAT1, which is involved in transport of APP. Another report has directly linked HSV1 and β-amyloid, showing the striking homology between sequences in the latter and a viral glycoprotein, gB, and the authors suggest that gB might act as a seed for amyloid deposition (Cribbs et al., 2000). Thus, there might be multiple interactions between HSV1 and APP. Indeed, we think that all these associations may be relevant rather than alternative mechanisms. One concern is that the APP identified by Satpute-Krishnan et al. almost certainly derives from the Vero (monkey kidney) cells used to grow the virus – although this is implied rather than specifically stated by the authors. Nonetheless, whatever the source of the protein, its association with HSV1 is exciting, indicating that it has a strong affinity for the components of the virus. It will be interesting to see whether HSV1 grown in more physiologically relevant cells – neurons, rather than Vero cells – is associated with APP, whether this APP is required for neuronal transport of the virus, and whether its own transport and degradation are affected. Satpute-Krishnan et al. do not discuss the possibility of direct involvement of APOE with HSV1 infection. They suggest several ways in which APOE might interact with APP, but our results show that it is APOE-ɛ4 together with HSV1 that confers a strong risk of AD (and consistently, we have found that APOE determines the effects of several other very different pathogens – see Itzhaki et al., 1997; Corder et al., 1998; Lin et al., 2001; Wozniak et al., 2002, 2003), i.e. the interaction of APOE with virus is equally important. Experiments to find if APOE does affect the phenomena described by Satpute-Krishnan et al. would therefore be of interest. Meanwhile, we propose a scheme involving APOE, APP and, more directly, HSV1, based on our work, on several recent epidemiological studies, and on HSV1 infection of APOE-transgenic mice: peripheral infections cause entry of cytokines into the brain and consequent inflammation; the latter reactivates latent HSV1 in brain and damage then ensues – perhaps through disturbed axonal transport of APP, deposition of β-amyloid and synaptic dysfunction, with the extent of damage (and age of onset) dependent on APOE genotype. The approaches used by Satpute-Krishnan et al. are likely to contribute significantly to future work examining the effects of HSV1 on synaptic function and on APP metabolism, thus helping to elucidate some major mechanisms underlying the development of AD." @default.
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• W4234334539 title "Commentary on 'Fast anterograde transport of Herpes Simplex Virus: Role for the amyloid precursor protein of Alzheimer's disease' by Prasanna Satpute-Krishnan et al. Aging Cell Vol. 2, Issue 6, 305-318 (2003)" @default.
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• W4234334539 doi "https://doi.org/10.1111/j.1474-9728.2004.00088.x" @default.
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