Abstract
A translational aging rat model for chronic aluminum (Al) neurotoxicity mimics human Al exposure by ingesting Al, throughout middle age and old age, in equivalent amounts to those ingested by Americans from their food, water, and Al additives. Most rats that consumed Al in an amount equivalent to the high end of the human total dietary Al range developed severe cognitive deterioration in old age. High-stage Al accumulation occurred in the entorhinal cortical cells of origin for the perforant pathway and hippocampal CA1 cells, resulting in microtubule depletion and dendritic dieback. Analogous pathological change in humans leads to destruction of the perforant pathway and Alzheimer's disease dementia. The hippocampus is thereby isolated from neocortical input and output normally mediated by the entorhinal cortex. Additional evidence is presented that Al is involved in the formation of neurofibrillary tangles, amyloid plaques, granulovacuolar degeneration, and other pathological changes of Alzheimer's disease (AD). The shared characteristics indicate that AD is a human form of chronic Al neurotoxicity. This translational animal model provides fresh strategies for the prevention, diagnosis, and treatment of AD.
Highlights
More than 36 million people are currently living with dementia worldwide [1] and about 75% of this population, that is, 27 million people, are estimated to be affected by Alzheimer’s disease (AD) [2]
A comparison of the health of older persons, described in the monograph Old Age published in Cambridge in 1889 [3] and papers published in the British Medical Journal between 1886 and 1889, with the health status of older persons today, raises the possibility that AD is a modern disease that has developed from altered living conditions associated with the industrialization of society [4]
This translational model demonstrates that chronic ingestion of Al, in amounts ingested by Americans from their food, water, and Al additives, is sufficient to induce AD-type cognitive deterioration in animals by old age
Summary
More than 36 million people are currently living with dementia worldwide [1] and about 75% of this population, that is, 27 million people, are estimated to be affected by Alzheimer’s disease (AD) [2]. The rats were trained at a young age to perform a rewarded continuous alternation T-maze task commonly used to assess memory function [11, 12]. Rats in the main study [8] were randomly assigned at age 12 months to three groups that consumed low, intermediate, and high Al levels in amounts equivalent to total dietary Al levels consumed by Americans from their food, water, and Al additives [13]. The only treatment difference was the amount of total dietary Al the three rat groups routinely consumed from their feed and water throughout middle age and old age [8]. Routine Al ingestion at these levels showed no significant effects on the animals’ kidney and liver functions [8]
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