A unifying hypothesis of Alzheimer's disease. II. Pathophysiological processes

The age-related loss of hormonal balance puts the homeostatic calcium-energ y-antioxidant triangle under stress. The energetic compromise enhances P-am yloid protein formation and tau protein hyperphosphorylation, both cellular stress responses, which may give rise to diffuse plaque and neurofibrillar y tangle formation during normal ageing. Facilitated by a multitude of risk factors (discussed in part III of this series), the age-related processes lead into the pathophysiological events of Alzheimer's disease (AD). In AD, the hormonal imbalance is further aggravated with progressively detrimenta l sequelae for the calcium-energy-redox homeostasis and for both amyloid pr otein precursor and tau protein metabolism. The immune system as an integra l component of the neuroendocrine immunological network is subject to the d eteriorating endocrinological balance and displays a cellular and humoral a cute phase-type reaction. In an orchestrated action, an inflammatory respon se is mounted in which activated micro- and astro-glia and their secreted i nflammatory mediators and matrix constituents elicit the transformation of diffuse into neuritic plaques which, secondarily, may induce further tissue damage. Importantly, the AD brain is characterized by the microglial inabi lity to clear the brain of the deposited material. The pathophysiological p rocesses lead to functional and structural impairments of neuronal plastici ty, a compromise of the neuronal network and, eventually, to cell death. Co nspicuously, these alterations do not uniformly affect all brain regions bu t manifest with a temporal and topographical specificity vulnerable areas a nd nerve cell populations. Copyright (C) 1999 John Wiley & Sons, Ltd.