Concordance of Several Subcellular Interactions Initiates Alzheimer's Dementia: Their Reversal Requires Combination Treatment

Abstract

The pathogenesis of Alzheimer's disease involves multiple pathways that, at the macrolevel, include decreased proliferation plus increased loss affecting neurons, astrocytes, and capillaries and, at the subcellular level, involve several elements: amyloid/amyloid precursor protein, presenilins, the unfolded protein response, the ubiquitin/proteasome system, the Wnt/catenin system, the Notch signaling system, mitochondria, mitophagy, calcium, and tau. Data presented show the intimate, anatomical interactions between neurons, astrocytes, and capillaries; the interactions between the several subcellular factors affecting those cells; and the treatments that are currently available and that might correct dysfunctions in the subcellular factors. Available treatments include lithium, valproate, pioglitazone, erythropoietin, and prazosin. Since the subcellular pathogenesis involves multiple interacting elements, combination treatment would be more effective than administration of a single drug directed at only 1 element. The overall purpose of this presentation is to describe the pathogenesis in detail and to explain the proposed treatments.

Keywords: Alzheimer’s; astrocytes; cerebral capillaries; neurons; subcellular mechanisms; treatments.

Figure 1.

Multiple interactions between the subcellular mechanisms affecting neurons, astrocytes and capillaries in Alzheimer’s disease. Note: The multiple interactions are usually bidirectional. Not all mechanisms may be active at any given time. NB: There is no intention to imply dominance of any one of the depicted mechanisms. Abbreviations: Mt = mitochondria; PS = presenilins; UPR = unfolded protein response; UPS = ubiquitin/proteasome system; Wnt = Wnt/β-catenin signaling system.