Considerable progress has been made in elucidating the molecules involved in the pathology of Alzheimer's disease (AD). However, it is still uncertain why the hippocampus is the focus of this pathology, since these molecules (amyloid precursor protein, beta secretase, apolipoprotein E) are not more abundant within the hippocampus than in other, undamaged brain areas. Several unique features of the hippocampus may make it more vulnerable to this age-related pathology. These include 1) a specialized metabolism that enhances damaging effects of oxidative stress, 2) a capacity for neurogenesis, and 3) specializations in mitochondrial and metal homeostasis. The thesis of this paper is that an unusual subset of hippocampal astrocytes makes a fundamental contribution to all three of these hippocampal features and allows different and seemingly conflicting risk factors for AD to be viewed in a unified manner. These astrocytes participate in neurogenesis, produce fatty acid binding protein 7, unlike most astrocytes in the mature brain, and undergo an age-related mitochondrial degeneration. Degeneration of astrocyte mitochondria appears due to oxidative stress arising from fatty acid metabolism. This mitochondrial degeneration produces intracellular deposits of iron and copper, metals that have been shown to harmfully interact with cleavage products of amyloid precursor protein. Pharmacological and dietary manipulations that protect these astrocytes from age-related oxidative stress may prove to be useful strategies in combatting the progression of AD.
Pubmed ID: 29255838 RIS Download
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