Alzheimer's Disease: From Firing Instability to Homeostasis Network Collapse

Alzheimer's disease (AD) starts from pure cognitive impairments and gradually progresses into degeneration of specific brain circuits. Although numerous factors initiating AD have been extensively studied, the common principles underlying the transition from cognitive deficits to neuronal loss remain unknown. Here we describe an evolutionarily conserved, integrated homeostatic network (IHN) that enables functional stability of central neural circuits and safeguards from neurodegeneration. We identify the critical modules comprising the IHN and propose a central role of neural firing in controlling the complex homeostatic network at different spatial scales. We hypothesize that firing instability and impaired synaptic plasticity at early AD stages trigger a vicious cycle, leading to dysregulation of the whole IHN. According to this hypothesis, the IHN collapse represents the major driving force of the transition from early memory impairments to neurodegeneration. Understanding the core elements of homeostatic control machinery, the reciprocal connections between distinct IHN modules, and the role of firing homeostasis in this hierarchy has important implications for physiology and should offer novel conceptual approaches for AD and other neurodegenerative disorders. The key driver of Alzheimer's pathophysiology remains controversial. Frere and Slutsky describe the integrated homeostasis network, composed of firing, genome, proteome, calcium, energy, and immune modules, that enables functional stability of neural circuits. The authors propose that firing homeostasis failure triggers a vicious cycle that dysregulates the whole homeostatic network, driving Alzheimer's degeneration.