Bilbo SD, Levkoff LH, Mahoney JH, Watkins LR, Rudy JW, Maier SF.
Neonatal infection induces memory impairments following an immune challenge in adulthood.
Behav Neurosci. 2005 Feb;119(1):293-301.
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My speculations about AD include the thought that AD has an extremely long presymptomatic period, which may extend into childhood. This is based on data such as the Braaks finding that 20 percent of people in their 20s have neurofibrillary tangles (NFT) and senile plaques (SP), though not meeting the criteria for AD. It is also based on our knowledge that NFT and SP represent only the most obvious of a sequence of more subtle changes in tau conformation and other post-translational modifications that certainly precede the formation of frank NFT; similarly for APP and Aβ, and SP.
Whether the metals and infectious agents mentioned in this news review are related to this sort of speculation is not at all certain. There are a number of subtle parameters that could be looked at that might be informative.
Infants and young children are subjected to a battery of infectious agents, including human herpes virus 6, herpes simplex virus type 1 (HSV1), adenoviruses, respiratory syncytial virus, rhinoviruses and probably enteroviruses, and these, as well as overt neonatal infections, might have long-term effects on the host. Further, these pathogens (like many others, e.g., poliovirus, West Nile virus, and the bacteria that cause TB, or stomach ulcers), can elicit a whole spectrum of responses depending on the host, infecting vastly more people than they seemingly affect, and some can remain lifelong in the host. Thus, even slight damage might be cumulative and long-term, even in people who appear asymptomatic. In other words, surreptitious persistent infection/disease needs to be considered as well as overt diseases of infancy. The same point relates to the hypothesis put forward by Finch and Crimmins, 2004, linking longevity to the prevention of childhood illnesses due to improved public health, etc., in the last half-century or so: Only certain major diseases have been prevented.
An interesting paper by Wang et al., 2005, may be relevant to the above and to our data implicating HSV1 in brain together with ApoE-ε4 as a risk factor in AD (Itzhaki et al., 1997; Dobson et al., 2003). Wang et al. find that peripheral infection with West Nile virus triggers a transient change in the permeability of the blood-brain barrier (BBB). Perhaps other pathogens cause such changes in BBB; certainly there is evidence that systemic infections lead to cytokine entry into brain, which in turn causes inflammation and cognitive decline in the elderly (Holmes et al., 2003), and we have suggested (Itzhaki et al., 2004) that the inflammation could reactivate latent HSV1, thereby augmenting the damage, just as subclinical prion disease in mice augments the brain damage caused by LPS injection (Combrinck et al., 2002).
Finch CE, Crimmins EM.
Inflammatory exposure and historical changes in human life-spans.
Science. 2004 Sep 17;305(5691):1736-9.
Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA.
Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis.
Nat Med. 2004 Dec;10(12):1366-73.
Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA.
Herpes simplex virus type 1 in brain and risk of Alzheimer's disease.
Lancet. 1997 Jan 25;349(9047):241-4.
Dobson CB, Wozniak MA, Itzhaki RF.
Do infectious agents play a role in dementia?.
Trends Microbiol. 2003 Jul;11(7):312-7.
Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH.
Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer's disease.
J Neurol Neurosurg Psychiatry. 2003 Jun;74(6):788-9.
Itzhaki RF, Wozniak MA, Appelt DM, Balin BJ.
Infiltration of the brain by pathogens causes Alzheimer's disease.
Neurobiol Aging. 2004 May-Jun;25(5):619-27.
Combrinck MI, Perry VH, Cunningham C.
Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease.
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