Department
of Neurology, Heinrich Heine University, Düsseldorf, Germany
This issue contains Part IV of Dr. Heininger’s
unifying hypothesis of Alzheimer’s disease [Heininger K. 1999. A unifying
hypothesis of Alzheimer’s disease. I. Ageing sets the stage. Hum
Psychopharmacol Clin Exp 14: 363-414; Heininger K. 1999. A unifying
hypothesis of Alzheimer’s disease. II. Pathophysiological processes. Hum
Psychopharmacol Clin Exp 14: 525-581; Heininger K. 2000. A unifying
hypothesis of Alzheimer’s disease. III. Risk factors. Hum Psychopharmacol
Clin Exp 15: 1-70].
Contrary
to common concepts, the brain in Alzheimer’s disease (AD) does not follow a
suicide but a rescue program. Widely shared features of metabolism in starvation,
hibernation and various conditions of energy deprivation allow the definition
of a deprivation syndrome which is a phylogenetically conserved, from bacteria
to man, adaptive response to energetic stress, characterized by hypometabolism,
oxidative stress and adaptive responses of the glucose-fatty acid cycle.
Evidence suggests that the brain in aging and AD actively adapts to progressive
fuel deprivation. The counterregulatory mechanisms aim to preserve glucose for
anabolic needs and promote the oxidative utilization of ketone bodies. The
agent mediating the metabolic switch is soluble Ab which
inhibits glucose utilization and stimulates ketone body utilization at various
levels. Hormonal and effector systems which promote ketone body utilization are
enhanced. A multitude of risk factors feed into this pathophysiological cascade
at a variety of levels. Taking into account its pleiotropic regulatory actions
in the deprivation response, a new name for Ab is
suggested: deprivin. Cumulative evidence suggests that senile plaques are the
dump rather than the driving force of AD. Moreover, the neurotoxic action of
fibrillar Ab is a likely in vitro artifact but does not
contribute significantly to the in vivo pathophysiological events.
This
archaic program aims to ensure the survival of a deprived organism and controls
such divergent processes as sporulation, hibernation, aging and aging-related
diseases. In contrast to the immature brain, ketone body utilization of the
aged brain is no longer sufficient to meet energetic demands and is later
supplemented by lactate, thus recapitulating in reverse order the sequential
fuel utilization of the immature brain. The transduction pathways which operate
to switch metabolism also convey the programming and balancing of the
de-/redifferentiation/apoptosis cell cycle decisions. This encompasses the
reiteration of developmental processes such as transcription factor activation,
tau hyperphosphorylation, and establishment of growth factor independence by
means of Ca2+ set point shift. Thus, the increasing energetic
insufficiency results in the progressive centralization of metabolic activity
to the neuronal soma, leading to pruning of axonal/dendritic trees, loss of
neuronal polarity, downregulation of neuronal plasticity and, eventually,
depending on Ca2+-energy-redox homeostasis, degeneration of
vulnerable neurons. Finally, it is outlined that genetic (e.g. Down’s syndrome,
APP and presenilin mutations and apoE4) and environmental risk factors
represent progeroid factors which accelerate the aging process and precipitate
the manifestation of AD as a progeroid systemic disease. Aging and AD are
related to each other by threshold phenomena, corresponding to stage 2, the
stage of resistance, and stage 3, exhaustion, of a metabolic stress response.
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ISSN 0334-1763/11-S1
120 pages
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