Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008 Jun;118(6):2190-9. PubMed.
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Comments
New York University School of Medicine/Nathan Kline Institute
The Pickford et al. study adds strong support to an emerging view that autophagic-lysosomal impairment in AD can contribute to Aβ pathology and also to neurodegeneration through additional Aβ-independent mechanisms, which might be shared by other neurological diseases across the lifespan (1). The deficiencies Pickford and colleagues identified in the initial “sequestration” stages of autophagy compound other defects. We previously reported the clearance of Aβ-generating autophagic vacuoles that lead to vacuole accumulation—even in the presence of possibly slowed autophagosome formation as implied by the current findings.
Protein/vesicular trafficking defects in AD tend to be viewed from the focused perspective of how APP metabolism is altered, but, as this and other recent studies imply, the trafficking/handling of many proteins is affected by alterations of endosomes, autophagic compartments, and lysosomes, which are increasingly being linked to AD-related genetic factors (e.g., presenilin, SorLA, APP duplication, etc.). These more global effects on neuronal function are the "elephant in the room" in most current discussions of altered protein/vesicular trafficking in AD and deserve consideration as factors relevant to AD pathogenesis in their own right. In this regard, the endosomal-autophagic lysosomal system dysfunction being recognized in a growing number of other neurodegenerative diseases may well inform us about the pathogenic significance of such impairments in AD.
References:
Nixon RA, Yang DS, Lee JH. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy. 2008 Jul;4(5):590-9. Epub 2008 May 12 PubMed.
Universities of Manchester and Oxford
Another Herpes Virus-Alzheimer’s Disease Connection: Beclin Beckons
This study not only strengthens the link between AD and autophagy by relating it to a reduced beclin 1 activity in the diseased brain. It also strengthens, indirectly, another link which we proposed (1), namely, among herpes simplex virus type 1 (HSV1), autophagy, and AD—thus extending the striking HSV1-amyloid connection that we recently discovered (2). HSV1 infects, and then resides lifelong, in the peripheral nervous system (PNS) of most humans in a latent state and is reactivated periodically by events such as stress; it then causes damage—cold sores—in some of those infected.
We detected HSV1 DNA some 18 years ago in the brain of many elderly humans (3), and subsequently showed that in brain, as in the PNS, it reactivates from latency (4), possibly recurrently, triggered presumably by stress, systemic infection, etc. Further, we found that HSV1 in ApoE-ε4 carriers’ brains conferred a strong risk of AD (5), and we suggested that brain damage caused on viral reactivation was greater in ApoE-ε4 carriers, leading to the development of AD (5,6). Since then, several studies by others have linked HSV1 to AD, detecting a close homology between a sequence in Aβ and one of the viral glycoproteins (7), and showing that APP associates with HSV1 during axonal transport (8). Also, recent studies have indicated that ApoE affects HSV1 (9-12), determining its transport in tissues and its expression. (Indeed, we have found that ApoE influences outcome of infection by several other viruses, including occurrence of cold sores in ApoE-ε4 carriers—paralleling the CNS situation—see, e.g., [6].)
Our recent data reveal that HSV1 infection of cultured cells causes a large accumulation of Aβ (2) and also AD-like tau phosphorylation, and infection of mice causes Aβ accumulation in brain.
Our recent hypothesis proposes that excess Aβ produced by HSV1 action is inadequately removed by autophagy because of viral hindrance, thus allowing plaque formation to occur (1). This was based on the fact that cells infected by HSV1 attempt to demolish the intruder by an autophagic process called xenophagy, but to evade this, the viral-encoded neurovirulence protein, ICP34.5, binds to beclin and inhibits its autophagic function (13). This ability to overcome xenophagy is shared by various other infectious agents, e.g., HIV (14) (and some microbes even use autophagy for their own advantage [15,16]), but HSV1 is the only pathogen (or indeed inflammation-producing agent) detected so far in many normal elderly human brains, and is therefore the only agent in a position to cause AD-like damage—as indeed we have shown it to do in cells and mice. In fact, one of the authors of the present study, too, has discussed the possibility that viral inhibition of autophagy might contribute to “non-infectious” neurodegenerative diseases such as AD (17).
References:
Itzhaki RF, Cosby SL, Wozniak MA. Herpes simplex virus type 1 and Alzheimer's disease: the autophagy connection. J Neurovirol. 2008 Jan;14(1):1-4. PubMed.
Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett. 2007 Dec 18;429(2-3):95-100. PubMed.
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Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF. Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer's disease patients. J Med Virol. 2005 Feb;75(2):300-6. PubMed.
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Itzhaki RF, Wozniak MA. Herpes simplex virus type 1 in Alzheimer's disease: the enemy within. J Alzheimers Dis. 2008 May;13(4):393-405. PubMed.
Cribbs DH, Azizeh BY, Cotman CW, Laferla FM. Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer's A beta peptide. Biochemistry. 2000 May 23;39(20):5988-94. PubMed.
Satpute-Krishnan P, DeGiorgis JA, Bearer EL. Fast anterograde transport of herpes simplex virus: role for the amyloid precursor protein of alzheimer's disease. Aging Cell. 2003 Dec;2(6):305-18. PubMed.
Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F. ApoE4 is more efficient than E3 in brain access by herpes simplex virus type 1. Neuroreport. 2003 Oct 6;14(14):1825-7. PubMed.
Burgos JS, Ramirez C, Sastre I, Valdivieso F. Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol. 2006 Jun;80(11):5383-7. PubMed.
Bhattacharjee PS, Neumann DM, Stark D, Thompson HW, Hill JM. Apolipoprotein E modulates establishment of HSV-1 latency and survival in a mouse ocular model. Curr Eye Res. 2006 Sep;31(9):703-8. PubMed.
Miller RM, Federoff HJ. Isoform-specific effects of ApoE on HSV immediate early gene expression and establishment of latency. Neurobiol Aging. 2008 Jan;29(1):71-7. PubMed.
Orvedahl A, Alexander D, Tallóczy Z, Sun Q, Wei Y, Zhang W, Burns D, Leib DA, Levine B. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe. 2007 Mar 15;1(1):23-35. PubMed.
Zhou D, Spector SA. Human immunodeficiency virus type-1 infection inhibits autophagy. AIDS. 2008 Mar 30;22(6):695-9. PubMed.
Colombo MI. Pathogens and autophagy: subverting to survive. Cell Death Differ. 2005 Nov;12 Suppl 2:1481-3. PubMed.
Wileman T. Aggresomes and autophagy generate sites for virus replication. Science. 2006 May 12;312(5775):875-8. PubMed.
Orvedahl A, Levine B. Autophagy and viral neurovirulence. Cell Microbiol. 2008 Sep;10(9):1747-56. Epub 2008 May 22 PubMed.
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