Abstract
The causes of Alzheimer’s disease (AD) and of the characteristic pathological features—amyloid plaques and neurofibrillary tangles—of AD brain are unknown, despite the enormous resources provided over the years for their investigation. Indeed, the only generally accepted risk factors are age, Down syndrome, carriage of the type 4 allele of the apolipoprotein E gene (APOE-ε4), and possibly brain injury. Following the authors’ previous studies implicating herpes simplex virus type 1 (HSV1) in brain of APOE-ε4 carriers as a major cause of AD, the authors propose here, on the basis of their and others’ recent studies, that not only does HSV1 generate the main components of amyloid plaques and neurofibrillary tangles (NFTs)—β-amyloid (Aβ) and abnormally phosphorylated tau but also, by disrupting autophagy, it prevents degradation of these aberrant proteins, leading to their accumulation and deposition, and eventually to AD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ball MJ (1982). Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved? Can J Neurol Sci 9: 303–306.
Baringer JR, Pisani P (1994). Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol 36: 823–829.
Bertrand P, Guillaume D, Hellauer L, Dea D, Lindsay J, Kogan S, Gauthier S, Poirier J (1993). Distribution of herpes simplex virus type 1 DNA in selected areas of normal and Alzheimer’s disease brains: a PCR study. Neurodegeneration 2: 201–208.
Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F (2003). ApoE4 is more efficient than E3 in brain access by herpes simplex virus type 1. Neuroreport 14: 1825–1827.
Burgos JS, Ramirez C, Sastre I, Valdivieso F (2006). Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol 80: 5383–5387.
Cassady KA, Gross M, Roizman B (1998). The secondsite mutation in the herpes simplex virus recombinants lacking the gamma134.5 genes precludes shutoff of protein synthesis by blocking the phosphorylation of eIF-2alpha. J Virol 72: 7005–7011.
Chang RC, Suen KC, Ma CH, Elyaman W, Ng HK, Hugon J (2002). Involvement of double-stranded RNA-dependent protein kinase and phosphorylation of eukaryotic initiation factor-2alpha in neuronal degeneration. J Neurochem 83: 1215–1225.
Chou J, Chen JJ, Gross M, Roizman B (1995). Association of a M(r) 90,000 phosphoprotein with protein kinase PKR in cells exhibiting enhanced phosphorylation of translation initiation factor eIF-2 alpha and premature shutoff of protein synthesis after infection with gamma 134.5-mutants of herpes simplex virus 1. Proc Natl Acad Sci U S A 92: 10516–10520.
Colombo MI (2005). Pathogens and autophagy: subverting to survive. Cell Death Differ 12(Suppl 2): 1481–1483.
Cribbs DH, Azizeh BY, Cotman CW, LaFerla FM (2000). Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer’s A beta peptide. Biochemistry 39: 5988–5994.
Cuervo AM, Bergamini E, Brunk UT, Droge W, French M, Terman A (2005). Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 1: 131–140.
Fodor PA, Levin MJ, Weinberg A, Sandberg E, Sylman J, Tyler KL (1998). Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology 51: 554–559.
Gordon L, McQuaid S, Cosby SL (1996). Detection of herpes simplex virus types 1 and 2 and human herpes virus 6 DNA in human brain tissue by polymerase chain reaction. Clin Diagnost Virol 6: 33–40.
Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441: 885–889.
Hemling N, Roytta M, Rinne J, Pollanen P, Broberg E, Tapio V, Vahlberg T, Hukkanen V (2003). Herpesviruses in brains in Alzheimer’s and Parkinson’s diseases. Ann Neurol 54: 267–271.
Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH (2003). Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74: 788–789.
Itabashi S, Arai H, Matsui T, Higuchi S, Sasaki H (1997). Herpes simplex virus and risk of Alzheimer’s disease. Lancet 349: 1102.
Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997). Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349: 241–244.
Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF (1991). Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 33: 224–227.
Jamieson GA, Maitland NJ, Wilcock GK, Yates CM, Itzhaki RF (1992). Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type. J Pathol 167: 365–368.
Klapper PE, Cleator GM, Longson M (1984). Mild forms of herpes encephalitis. J Neurol Neurosurg Psychiatry 47: 1247–1250.
Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880–884.
Konsman JP, Parnet P, Dantzer R (2002). Cytokineinduced sickness behaviour: mechanisms and implications. Trends Neurosci 25: 154–159.
Lin WR, Graham J, MacGowan SM, Wilcock GK, Itzhaki RF (1998). Alzheimer’s disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimer’s Rep 1: 173–178.
Marques AR, Straus SE, Fahle G, Weir S, Csako G, Fischer SH (2001). Lack of association between HSV-1 DNA in the brain, Alzheimer’s disease and apolipoprotein E4. J NeuroVirol 7: 82–83.
Martinez-Vicente M, Sovak G, Cuervo AM (2005). Protein degradation and aging. Exp Gerontol 40: 622–633.
Miller RM, Federoff HJ (2008). Isoform-specific effects of ApoE on HSV immediate early gene expression and establishment of latency. Neurobiol Aging 29: 71–77.
Mori I, Kimura Y, Naiki H, Matsubara R, Takeuchi T, Yokochi T, Nishiyama Y (2004). Reactivation of HSV-1 in the brain of patients with familial Alzheimer’s disease. J Med Virol 73: 605–611.
Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM (2005). Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64: 113–122.
Peel AL (2004). PKR activation in neurodegenerative disease. J Neuropathol Exp Neurol 63: 97–105.
Rodriguez JD, Royall D, Daum LT, Kagan-Hallet K, Chambers JP (2005). Amplification of herpes simplex type 1 and human herpes type 5 viral DNA from formalin-fixed Alzheimer brain tissue. Neurosci Lett 390: 37–41.
Satpute-Krishnan P, DeGiorgis JA, Bearer EL (2003). Fast anterograde transport of herpes simplex virus: role for the amyloid precursor protein of Alzheimer’s disease. Aging Cell 2: 305–318
Strandberg TE, Pitkala KH, Linnavuori KH, Tilvis RS (2003). Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke 34: 2126–2131.
Talloczy Z, Jiang W, Virgin HW, Leib DA, Scheuner D, Kaufman RJ, Eskelinen EL, Levine B (2002). Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci U S A 99: 190–195.
Talloczy Z, Virgin HW, Levine B (2006). PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2: 24–29.
Ward WF (2002). Protein degradation in the aging organism. Prog Mol Subcell Biol 29: 35–42.
Wileman T (2006). Aggresomes and autophagy generate sites for virus replication. Science 312: 875–878.
Wozniak MA, Itzhaki RF, Faragher EB, James MW, Ryder SD, Irving WL (2002). Apolipoprotein Eepsilon 4 protects against severe liver disease caused by hepatitis C virus. Hepatology 36: 456–463.
Wozniak, Itzhaki, Shipley, Dobson (2007). Herpes simplex virus infection causes cellular beta amyloid accumulation and secretase upregulation, is now published: Neurosci Lett 429: 95–100.
Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF (2005). Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer’s disease patients. J Med Virol 75: 300–306.
Yu WH, Kumar A, Peterhoff C, Shapiro Kulnane L, Uchiyama Y, Lamb BT, Cuervo AM, Nixon RA (2004). Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for betaamyloid peptide over-production and localization in Alzheimer’s disease. Int J Biochem Cell Biol 36: 2531–2540.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Itzhaki, R.F., Cosby, S.L. & Wozniak, M.A. Herpes simplex virus type 1 and Alzheimer’s disease: The autophagy connection. Journal of NeuroVirology 14, 1–4 (2008). https://doi.org/10.1080/13550280701802543
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1080/13550280701802543