The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review.
Aging of the brain has been demonstrated to be the main risk factor for late-onset sporadic AD what is in contrast to early-onset familial AD in which mutations predominate the pathology. Aging of the brain was found to be associated with a multitude of aberrancies from normal in morphological, cellular and molecular terms. Recent findings provide clear evidence that the function of the neuronal insulin/insulin receptor signal transduction cascade is of pivotal significance to maintain normal cerebral blood flow and oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and the cell cycle in terminally differentiated neurons no longer in the cell cycle. It has become evident that normal metabolism of both amyloid precursor protein and tau-protein is part of interactive processes controlled by the neuronal I/IR signal transduction cascade. In normal brain aging, the function of this cascade starts to fail compared to normal resulting in adverse effects in CBF/oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and cell cycle. The aberrancies may not be drastic, but multifold and permanently existing, inclusive the metabolism of APP and tau-protein. The amount of intraneuronally formed betaA4 may increase, and tau-protein may become hyperphosphorylated. These processes as a whole may increase the vulnerability of the aging brain and may facilitate the generation of late-onset sporadic AD.
Department of Pathochemistry and General Neurochemistry, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Federal Republic of Germany. siegfried_hoyer@med.uni-heidelberg.de
Siegfried
S
Hoyer
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000209:etiology*; D001921:Brain / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D010101:Oxygen Consumption; D011972:Receptor, Insulin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D007328:Insulin; D011972:Receptor, Insulin