Multicellular hypothesis for the pathogenesis of Alzheimer's disease

Abstract

Extensive abnormal interactions among microglia, astrocytes, and neurons of the CNS have been observed in proteinopathic neurodegenerative dementias of the elderly. These multicellular interactions are initiated by insoluble tangles of phosphorylated tau protein and plaques of amyloid peptides. Most research has focused on these neurotoxic proteins, but much less is known about the pathogenic roles of the responding resident and recruited neural cells. Principal interactions among the major 3 sets of CNS cells are herein considered at several levels in relation to cellular phenotypic alterations, mechanisms of cellular communication, and extent of involvement in the pathogenesis of Alzheimer's disease and related proteinopathic dementias. It remains to be determined which of these abnormal neurocellular phenomena are primary events and sufficiently contributory to neurodegeneration to be useful targets for therapy of senile dementias.-Goetzl, E. J., Miller, B. L. Multicellular hypothesis for the pathogenesis of Alzheimer's disease.

High complement levels in astrocyte‐derived exosomes of Alzheimer disease

“…Neuronal supportive functions of astrocytes include promotion of development, nutrition, survival, dendrite outgrowth and synapse formation 1-3 . Most inflammatory, neurodegenerative and ischemic diseases of the CNS elicit a highly coordinated multicellular response that encompasses an increase in the total number of astrocytes and their differentiation into reactive astrocytes of inflammatory type A1 and/or ischemia-related type A2 4-6 . Activated microglia are critical inducers of A1 inflammatory-neurotoxic astrocytes through NFκB-dependent pathways and a range of cytokines, but a greater understanding of mechanisms and specific mediators is still emerging 7-9 .…”

Deficient neurotrophic factors of CSPG4‐type neural cell exosomes in Alzheimer disease

“…Accumulated evidence strongly suggests that all CNS cells are adversely affected by Alzheimer disease (AD) (1)(2)(3)(4). The resultant abnormalities of astroglial cells and damaged neurons, as well as their interactions, are being unraveled, but it is not clear if any type of CNS cell is responsible for the protection and improved survival of neurons in proteinopathic neurodegenerative diseases and whether such functions are altered by AD.…”

Traumatic brain injury increases plasma astrocyte‐derived exosome levels of neurotoxic complement proteins

“…Astrocytes are abundant glial cells in the human central nervous system (CNS) that normally support the neurons through promotion of development, nutrition, survival, dendrite outgrowth, and synapse formation . CNS responses to neuroinflammatory and neurodegenerative diseases include elevation in the total number of astrocytes and their increased differentiation into A1‐type reactive astrocytes . An ensemble of immune cytokines are prominent inducers of A1‐type astrocytes .…”

“…[1][2][3] CNS responses to neuroinflammatory and neurodegenerative diseases include elevation in the total number of astrocytes and their increased differentiation into A1-type reactive astrocytes. [4][5][6] An ensemble of immune cytokines are prominent inducers of A1-type astrocytes. [7][8][9] A1type astrocytes exhibit increased expression of pro-inflammatory pathways as well as neuron-directed toxic activities that damage synapses early and later destroy the neurons.…”