Hypothesis regarding amyloid and zinc in the pathogenesis of Alzheimer disease: potential for preventive intervention.
In Alzheimer disease (AD) the "primum movens" is amyloid (AM) production within the cerebral cortex. Cerebral AM alone may be asymptomatic. Clinical symptoms (amnesia, instrumental disorders) appear when AM induces neighboring neuritic alterations: paired hellical filaments (PHF), and distant neuronal body lesions; neurofibrillary tangles (NFT), i.e. pathologic synthesis of abnormal proteins. The timing for these inductions should be equal to the survival after the onset of amnesia: a mean of 14 months for the induction of the peri-AM neuritic alterations and a mean of 52 months for the induction of the distant to AM NFT in the hippocampic neuronal bodies. We postulate that the AM induces this neuronal pathology by producing functional zinc deficiency. The hippocampal zinc decreases in AD. The mechanism of the AM-induced zinc deficiency may be the following: the AM is formed within the walls of capillaries (senile plaques), disturbs the blood-brain barrier (BBB) and toxic metals (i.e., iron, aluminum, mercury) may enter in the cerebral cortex, where they displace the zinc in some enzymes. NFT and neuronal dysfunction may be produced by deficiency of the following zinc enzymes: (a) those of DNA metabolism, inducing abnormal DNA in the neurons and therefore abnormal protein synthesis, PHF-NFT; (b) those of glutamate (GLU) dehydrogenase (which catabolizes GLU), resulting in an excitotoxic increase of GLU; (c) those of neuronal detoxification, superoxydedismutase, carbonic anhydrase, and lactate dehydrogenase leading to neuronal toxicity. During the window between AM formation and PHF-NFT production (14-52 months), a zinc complex crossing the BBB may be useful to prevent AM of producing PHF-NFT, and also to normalize neuronal detoxification.(ABSTRACT TRUNCATED AT 250 WORDS)
Constantinidis
J
J
Department of Psychiatry, Morphological Psychopathology, University of Geneva Medical School, Switzerland.
D000368:Aged; D000544:Alzheimer Disease / Q000503:physiopathology* / Q000517:prevention & control; D000682:Amyloid / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000502:physiology; D002540:Cerebral Cortex / Q000503:physiopathology; D006801:Humans; D012307:Risk Factors; D015032:Zinc / Q000502:physiology*
D000682:Amyloid; D015032:Zinc