Neurodegenerative Disease Alzheimer’s Disease
environmental risk factors have been associated with the precocious development of AD. Given the fact that epilepsy is often one of the consequences of head injury, it is likely that these problems exacerbate and/or hasten the precocious development of neuropathological changes of AD.
Indeed, this is the case when either epilepsy or head injury is assessed with regard to the influence of inheritance of an APOE ε4 allele; such inheritance adds to the risk for a poor outcome in both epilepsy and head injury.158,159
as wide ranging as:
• heart disease;160 • AIDS;161,162 • obesity and diabetes;126,163–168
Discovery of proinflammatory activity exhibited by sAPP provided the missing link between the two universal responses of neural systems to injury: increased neuronal expression of APP and glial activation with excess cytokine expression. Namely, injury-induced overproduction of sAPP provides for a progressive feed-forward cycle whereby the resultant microglial activation and release of IL-1 leads to further βAPP elevation.
Conditions associated with an increased risk for AD are and • hypertension and heart disease.165,168–170
As with head injury and epilepsy, the risks conferred are increased in carriers of one or more APOE ε4 alleles.164,170,171
In addition, head injury,
epilepsy, and AIDS include early overexpression of βAPP and increases in neuroinflammatory cytokines, such as IL-1 and S100B.82,172–177
In several
of the conditions mentioned above, glial activation has been associated with neuropathological changes similar to those in AD; glial activation is sometimes present long before frank neurodegeneration is noted. Conditions involving glial activation include:
• DS;56,57 • head injury;172,175 • epilepsy;176,177 • obesity and diabetes;126,166,167
• AIDS.178 Summary
The pervasive appearance of glial activation and proinflammatory cytokine overexpression prior to and accompanying the neuropathological changes of AD suggests their importance in its development. The known capacity of at least one of these cytokines—IL-1—to induce expression of other cytokines and the hallmarks of AD neuropathology highlights cytokine importance in Alzheimer’s pathogenesis.
1. 2.
Glenner GG, Wong CW, Quaranta V, et al., The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis, Appl Pathol, 1984;2:357–69.
Glenner GG, Wong CW, Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem Biophys Res Commun, 1984;120:885–90.
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Gorevic PD, Castano EM, Sarma R, et al., Ten to fourteen residue peptides of Alzheimer’s disease protein are sufficient for amyloid fibril formation and its characteristic x-ray diffraction pattern, Biochem Biophys Res Commun, 1987;147:854–62.
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Gorevic PD, Goñi F, Pons-Estel B, et al., Isolation and partial characterization of neurofibrillary tangles and amyloid plaque core in Alzheimer’s disease: immunohistological studies, J Neuropathol Exp Neurol, 1986;45:647–64.
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W Sue T Griffin, PhD, is a Professor of Geriatrics, Neurobiology and Developmental Sciences at the University of Arkansas for Medical Sciences and Research Health Scientists in the Geriatric Research Education and Clinical Center at the Central Arkansas Veterans Healthcare System. Dr Griffin is also Editor in Chief of the Journal of Neuroinflammation. Her discovery of excess production of glial cytokines in Alzheimer’s disease and early on in Down syndrome, led to conceptualization of a self-propagating
cytokine cycle that defined the roles of specific cytokines in Alzheimer pathogenesis. Dr Griffin’s doctorate in physiology is from the University of Rochester School of Medicine.
and
Steven W Barger, PhD, is a Professor of Geriatrics, Neurobiology, and Developmental Sciences at the University of Arkansas for Medical Sciences and Research Health Scientists in the Geriatric Research Education and Clinical Center at the Central Arkansas Veterans Healthcare System. Dr Barger’s research focuses on two hypotheses regarding the role of neurotransmission in the initiation and progression of Alzheimer's disease. He has documented the untoward release of excitatory neurotransmitters by
activated microglia. More recently, Dr Barger’s work has elucidated mechanisms by which this excitatory neurotransmission intersects with downstream signaling events modulated by apolipoprotein E. Dr Barger received his doctorate in Cell Biology from Vanderbilt University.
Knowledge of the mechanisms involved in this link has provided a framework for understanding the way in which neuronal-glial interactions culminate in AD. Moreover, this also explains, at least in part, why neuronal trauma sets a cycle in motion. Neuronal trauma can be induced by untoward genetic inheritance, direct injury, comorbid conditions or as-yet unknown factors. The self-propagating cycle, properly called the cytokine cycle, promotes chronic production of glial cytokines, precursors of Aβ plaques, neurofibrillary tangles, Lewy bodies, the buildup of unwanted proteins and cognitive decline. n
Watkins PC, Tanzi RE, Cheng SV, et al., Molecular genetics of human chromosome 21, J Med Genet, 198724:257–70.
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St George-Hyslop PH, Tanzi RE, Polinsky RJ, et al., The genetic defect causing familial Alzheimer’s disease maps on chromosome 21, Science, 1987;235:885–90.
Cheng SV, Nadeau JH, Tanzi RE, et al., Comparative mapping of DNA markers from the familial Alzheimer disease and Down syndrome regions of human chromosome 21 to mouse chromosomes 16 and 17, Proc Natl Acad Sci U S A, 1988;85:6032–6.
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Cruts M, Hendriks L, Van Broeckhoven C, The presenilin genes: a new gene family involved in Alzheimer disease pathology, Hum Mol Genet, 1996;5:1449–55.
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Kovacs DM, Fausett HJ, Page KJ, et al., Alzheimer- associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells, Nat Med, 1996;2:224–9.
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Sherrington R, Rogaev EI, Liang Y, et al., Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease, Nature, 1995;375:754–60.
Levy-Lahad E, Wasco W, Poorkaj P, et al., Candidate gene for the chromosome 1 familial Alzheimer’s disease locus, Science, 1995;269:973–7.
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US NEUROLOGY
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