Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH. Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci. 2008 Jan 2;28(1):3-9. PubMed.
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Emory University
The developing brain is particularly sensitive to environmental insults, including infection, radiation, and toxins. Because the brain is still growing, differentiating, and establishing connections at this time, such hazards can influence brain structure and function throughout the lifespan. For example, the risk of schizophrenia, a disorder that generally emerges in early adulthood, appears to be increased by specific maternal infections prenatally (Brown, 2006). Relatively little research has addressed the question of whether Alzheimer disease and other age-associated neurodegenerative disorders also might be promoted by brain changes incurred during development.
While the results involve a small number of animals and should be viewed as preliminary, the study of Wu and colleagues opens the door for further work in this area. These researchers studied the brains of eight female cynomolgus monkeys (Macaca fascicularis), four of which were exposed to low but biologically significant levels of lead acetate for the first 400 days of life. The animals showed no obvious health impairments over the ensuing years, but postmortem evaluation of the brains at 23 years of age found elevated mRNA for β-amyloid precursor protein (APP), the transcription factor Sp1, and (with borderline significance) β-amyloid cleaving enzyme-1 (BACE1) (the APP695 amino acid sequence in Macaca fascicularis is 100 percent homologous to human APP695). Aβ42 and Aβ40 levels, as well as the Aβ42:Aβ40 ratio, also were increased. In addition, DNA methyltransferase activity was decreased, and oxidative DNA damage increased, in the brains of lead-exposed monkeys. Future histological analysis of Aβ in similar tissues might benefit from a more rigorous definition of the brain areas and cortical layers analyzed, since the distribution of intracellular and extracellular Aβ immunoreactivity can vary substantially among regions.
These initial findings suggest that early lead exposure can promote the conditions for neurodegeneration-associated mechanisms later in life, and as such warrant further investigation. In addition, it is worth asking whether other types of early-life insult might have similar effects. Epidemiological studies could be informative in this regard, as has been the case for schizophrenia. Transgenic mouse models of AD-like pathogenesis also will be useful in accelerating the analysis of latent developmental influences and their mechanisms.
References:
Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006 Apr;32(2):200-2. PubMed.
Northwestern University, Feinberg School of Medicine
In this report, Wu et al. provide intriguing evidence that lead exposure during early postnatal life in female Macaca Fascicularis monkeys results in altered DNA methylation, oxidative stress, and changes related to amyloid pathology in late life. Expression of the genes for the amyloid precursor protein (APP) and its transcriptional regulator Sp1 was elevated in old animals that had been exposed to lead early during postnatal development. Significantly, these changes translated into elevated levels of the amyloid-β (Aβ) peptide, its intracellular accumulation, and increased deposition in cored plaques. These results replicate the author’s earlier findings in the rodent. These observations are provocative and enhance the possibility that early prenatal and/or postnatal events play a crucial role in initiation of disease. They invoke the probability that events in early life, including lead exposure, contribute to Alzheimer disease (AD) in late life. This line of research is worthy of pursuit in a larger cohort and as epidemiological study in humans.
Lary Walker has already commented on the strengths and a few shortcomings of this report. Here, a few additional cautionary notes are presented in relation to the interpretation of the findings. While the macaque species display Aβ deposits in the brain when they age, they cannot be considered a model of AD. Rather, more accurately, they should be considered a model of human aging. We have shown that, similar to many aged human brains, those of rhesus monkeys (a cousin of the Macaca Fascicularis) display primarily diffuse plaques as they age (1). Less than 20 percent of plaques in these aged animals are of the compact, pathological variety, which predominate in AD. A question in relation to the Wu et al. report is whether lead exposure during development merely results in increased pathology of aging or can actually lead to AD. Lack of quantitative analysis of the pathology in this report does not allow such a determination. Moreover, the predominant Aβ species in the macaque species is Aβ1-40 as opposed to that in human aging and AD, which is Aβ1-42 (1,2). In this light, the increased Aβ42/40 ratio reported in lead-exposed monkeys is intriguing.
A primary difference between macaque brain aging and human aging/AD is that it has been impossible to convincingly demonstrate the presence of tangles in the former, using the methods employed to visualize these structures in aged human brain and AD. Wu et al. report that lead exposure in developing animals resulted in structures with the morphology of tangles at old age. If true, this would be a major finding. Unfortunately, this observation only receives passing mention in this report. No picture of tangles is shown, no quantitative analysis of tau is provided, and the Congo red method used is not very sensitive for this purpose. If substantiated, this single finding would be a clearer indication of the contribution of lead exposure to AD pathology as compared with alterations in Aβ, because tangle formation shows a more robust relationship with cognitive status in AD than amyloid load and plaque formation. Significantly, Aβ load in macaque monkeys shows no relationship to age-related cognitive deficits observed in these animals (3).
Despite the above caveats, the report by Wu et al. raises important possibilities, and continued attention to this line of research is likely to provide valuable insights into developmental origins of diseases such as AD.
References:
Sani S, Traul D, Klink A, Niaraki N, Gonzalo-Ruiz A, Wu CK, Geula C. Distribution, progression and chemical composition of cortical amyloid-beta deposits in aged rhesus monkeys: similarities to the human. Acta Neuropathol. 2003 Feb;105(2):145-56. PubMed.
Gearing M, Tigges J, Mori H, Mirra SS. A beta40 is a major form of beta-amyloid in nonhuman primates. Neurobiol Aging. 1996 Nov-Dec;17(6):903-8. PubMed.
Sloane JA, Pietropaolo MF, Rosene DL, Moss MB, Peters A, Kemper T, Abraham CR. Lack of correlation between plaque burden and cognition in the aged monkey. Acta Neuropathol. 1997 Nov;94(5):471-8. PubMed.
This new study indicates "evidence for a developmental origin and environmental link for Alzheimer's disease." The major unresolved question is the timing and the triggering leading to the disease, but data does suggest that a pathogenesis is influenced by early life exposures, with results not significant until later in life.
Genetic celiac disease has long been associated with neurologic and psychiatric disorders. Mayo Clinic has discovered a relationship of CD and dementia. When I was diagnosed with CD 6 years ago, at the age of 75, it was also revealed that in addition to my mother's autopsy in 1980 for AD, she possessed the gene responsible for my currently disabling CD.
I am aware that the past deaths of eight family members were attributed to "dementia," with the four most recent of those diagnosed as AD. My sibling has currently also been diagnosed with AD, as well as possessing a genetic celiac gene.
This new evidence of an environmental trigger to AD would warrant a study of gluten toxicity as a possible foundation.
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