Is Alzheimer's disease an anterograde degeneration, originating in the brainstem, and disrupting metabolic and functional interactions between neurons and glial cells?

A novel hypothesis is suggested for the pathogenesis of Alzheimer's disease, i.e. that a degeneration of adrenergic neurons in locus coeruleus and/or of serotonergic neurons in the raphe nuclei leads to impairment in metabolic and functional interactions between neurons and astrocytes (in the cerebral cortex and hippocampus as well as in nucleus basalis magnocellularis), and that a resulting deficient supply of substrates and failing energy metabolism in both neurons and astrocytes causes neuronal cell death in these areas and thus interference with additional transmitter systems. The hypothesis is based on (1) the topographical distribution of ascending pathways from locus coeruleus and the raphe nuclei; (2) the peculiar termination of many of these fibres in varicosities, from which released transmitter molecules reach their targets by diffusion, rather than in genuine synapses, suggesting a partly non-neuronal target; (3) the effects of locus coeruleus lesions in experimental animals; (4) the emergence of new knowledge in cellular neurobiology, indicating profound metabolic and functional interactions between neurons and astrocytes; and (5) the effects of adrenergic and serotonergic agonists upon metabolism and function in rodent astrocytes and neurons. These compounds influence energy metabolism, membrane transport of potassium and production of growth factors in astrocytes, and glutamate release from glutamatergic neurons. They thus influence essential metabolic interactions between neurons and astrocytes, as well as neuronal-astrocytic interactions in potassium homeostasis at the cellular level. Obviously, neither the individual findings alone, nor their combination into a conceptual framework, prove the correctness of the hypothesis. However, they do provide a basis for further experimental work, using postmortem brain tissue from Alzheimer's patients and lesion studies in rodents, which can confirm or refute the hypothesis.