The last year saw some very exciting developments in Alzheimer's research. Among them, the relationship of inflamation processes to cognitive decline and a possible relationship of the herpes simplex virus in the presence of a certain genotype to the development of Alzheimers.
Simon Cooke, who writes a blog called the "Accidental Scientist," has posted a very readable and informative summary of some of the most interesting highlights of the latest research. He does a great job of explaining the new discoveries, and speculates about links between infectious diseases and chronic diseases yet to be confirmed. In particular his post on the use of an anti-inflammatory drug to treat Alzheimers - in minutes!, and his post on the possible role of Herpes in many chronic diseases are particularly worth reading.
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Posted by ellen at January 11, 2008 11:39 AM
I've rounded up some of the relevant citations and abstracts to help paint a picture of the new directions in this research.
Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction.
TNF causes apoptotic cell death, cellular proliferation, differentiation, inflammation, tumorigenesis, and viral replication.
TNF's primary role is in the regulation of immune cells.
Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human diseases, as well as cancer.[1]
Cytokines are group of kinetic proteins and peptides that are used in organisms as signaling compounds. These chemical signals are similar to hormones and neurotransmitters, and are used to allow one cell to communicate with another...
APOE[2] is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition.
Herpes virus (HSV-1) in the presence of gene appears to cause predisposition to developing Alzheimer's
NEUROBIOLOGY OF AGING Volume: 29 Issue: 1 Pages: 71-77 Published: JAN 2008
Alzheimer's disease (AD) is a common and devastating neurodegenerative disease in which most cases are of unknown, sporadic origin. In addition to age, the most prevalent known risk factor for developing AD is carriage of the 84 allele of Apolipoprotein E (ApoE). Carriage of the epsilon 2 or epsilon 3 allele of ApoE confers protection or no change in risk for AD, respectively. Latent herpes simplex virus type 1 (HSV-1) infection in the brain concurrent with ApoE4 carriage exacerbates risk for AD, suggesting that these two factors interact to promote neuronal dysfunction and degeneration in selective brain areas. ...
...Our data support the concept that HSV-1 and ApoE4 interact to provide an environment conducive to the development and/or spread of AD.
This is a commentary on a small trial in 15 patients that used spinal injections of an antiinflammatory drug "Etaniercept" and had a positive effect within minutes of administration on cognitive function .
Commentary
Perispinal etanercept: Potential as an Alzheimer therapeutic
W. Sue T. Griffin
Journal of Neuroinflammation 2008, 5:3doi:10.1186/1742-2094-5-3
Published: 10 January 2008
Tumor necrosis factor-alpha (TNF) is one of a number of systemic and immunomodulating cytokines that generally act to promote acute-phase reactions but can drive degenerative changes when chronically elevated. Traditional focus on TNF has been directed at these inflammation-related functions. ...
... More recent data have revealed that TNF, one of the few gliotransmitters, has strikingly acute effects on synaptic physiology. These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation, and synaptic dysfunction. Toward such manipulation in Alzheimer's disease, a six-month study was conducted with 15 probable-Alzheimer patients who were treated weekly with perispinal injection of Etanercept, an FDA-approved TNF inhibitor that is now widely used for treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for Alzheimer patients. Additionally, the authors were impressed by the striking rapidity with which these improvements occurred in the study patients. An example of this rapid improvement is presented in this issue as a case report by Tobinick and Gross. Such rapid gain of function inspires speculation about the role of gliotransmission or other equally rapid synaptic events in the relationship of TNF to Alzheimer-impacted neurophysiology. Because of the inability of large molecules such as etanercept to cross the blood brain barrier following conventional systemic administration, it is likely that the more direct drug delivery system pioneered by Tobinick also contributed to the effectiveness of the treatment. If so, this system could be useful in drug delivery to the brain in other neural disorders...
TNF-alpha Modulation for Treatment of Alzheimer's Disease: A 6-Month Pilot Study
Edward Tobinick, MD; Hyman Gross, MD; Alan Weinberger, MD; Hart Cohen, MD, FRCPC
Medscape General Medicine. 2006;8(2):25. ©2006 Medscape
Posted 04/26/2006
MedGenMed Neurology & Neurosurgery
...To investigate the use of a biologic TNF-alpha inhibitor, etanercept was given by perispinal extrathecal administration for the treatment of AD....This was a prospective, single-center, open-label, pilot (proof-of-concept) study, in which 15 patients with mild-to-severe AD were treated for 6 months. We administered etanercept, 25-50 mg, once weekly by perispinal administration. ...The average age of our patient population was 76.7....An increasing amount of basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of AD. This small, open-label pilot study suggests that inhibition of the inflammatory cytokine TNF-alpha may hold promise as a potential approach to AD treatment. Further study in randomized, placebo-controlled clinical trials is merited.
An article from 2004 discussing the role of herpes simplex virus type 1 and the bacterium Chlamydia pneumoniae as risk factors for AD.
http://dx.doi.org/10.1016/j.neurobiolaging.2003.12.021
Infiltration of the brain by pathogens causes Alzheimer’s disease
Neurobiology of Aging
Volume 25, Issue 5, May-June 2004, Pages 619-627
Challenging Views of Alzheimer's Disease - Round II
Despite very numerous studies on Alzheimer’s disease (AD), especially on amyloid plaques and neurofibrillary tangles, little information has been obtained thus on the causes of the disease. Evidence is described here that implicates firstly herpes simplex virus type 1 (HSV1) as a strong risk factor when it is present in brain of carriers of the type 4 allele of the gene for apolipoprotein E (APOE-4). Indirect support comes from studies indicating the role of APOE in several diverse diseases of known pathogen cause.
A second putative risk factor is the bacterium, Chlamydia pneumoniae. This pathogen has been identified and localized in AD brain. Current studies aimed at “proof of principle” address the entry of the organism into the CNS, the neuroinflammatory response to the organism, and the role that the organism plays in triggering AD pathology. An infection-based animal model demonstrates that following intranasal inoculation of BALB/c mice with C. pneumoniae, amyloid plaques/deposits consistent with those observed in the AD brain develop, thus implicating this infection in the etiology of AD.
Isoform-specific effects of ApoE on HSV immediate early gene expression and establishment of latency
Author(s): Miller RM (Miller, R. M.), Federoff HJ (Federoff, H. J.)
Source: NEUROBIOLOGY OF AGING Volume: 29 Issue: 1 Pages: 71-77 Published: JAN 2008
Abstract: Alzheimer's disease (AD) is a common and devastating neurodegenerative disease in which most cases are of unknown, sporadic origin. In addition to age, the most prevalent known risk factor for developing AD is carriage of the 84 allele of Apolipoprotein E (ApoE). Carriage of the epsilon 2 or epsilon 3 allele of ApoE confers protection or no change in risk for AD, respectively. Latent herpes simplex virus type 1 (HSV-1) infection in the brain concurrent with ApoE4 carriage exacerbates risk for AD, suggesting that these two factors interact to promote neuronal dysfunction and degeneration in selective brain areas. I...
We-find that carriage of the different ApoE alleles dramatically affects HSV-1 immediate early gene expression as well as the establishment of latency. ...Our data support the concept that HSV-1 and ApoE4 interact to provide an environment conducive to the development and/or spread of AD.
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