Re-thinking the Etiological Framework of Neurodegeneration

Abstract

Neurodegenerative diseases are among the leading causes of disability and death worldwide. The disease-related socioeconomic burden is expected to increase with the steadily increasing life expectancy. In spite of decades of clinical and basic research, most strategies designed to manage degenerative brain diseases are palliative. This is not surprising as neurodegeneration progresses "silently" for decades before symptoms are noticed. Importantly, conceptual models with heuristic value used to study neurodegeneration have been constructed retrospectively, based on signs and symptoms already present in affected patients; a circumstance that may confound causes and consequences. Hence, innovative, paradigm-shifting views of the etiology of these diseases are necessary to enable their timely prevention and treatment. Here, we outline four alternative views, not mutually exclusive, on different etiological paths toward neurodegeneration. First, we propose neurodegeneration as being a secondary outcome of a primary cardiovascular cause with vascular pathology disrupting the vital homeostatic interactions between the vasculature and the brain, resulting in cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (EV)-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases.

Keywords: body–brain trophism; dysbiosis; lifespan; senescence; vascular pathology.

FIGURE 1

Senescence-mediated neurodegeneration. Cellular senescence can be induced by several stimuli in the different brain cells. Senescence of microglia and astrocytes results in inflammation and the loss of trophic support. Oligodendrocyte senescence reduces myelin, which affects transmission and the BBB may be compromised by endothelial cells senescence. These changes have an impact on the integrity and viability of neurons and ultimately brain function [based on Chinta et al. (2015)]. SASP, senescence-associated secretory phenotype.

FIGURE 2

The role of trophic interactions between the brain and the body in the development of neurodegenerative diseases. Under physiologic conditions, there is a continuous exchange of information between neurons and their targets. Neurons control several aspects of the cells they innervate by the release of neuropeptides and neurotransmitters. Reciprocally, peripheral cells modulate neuronal physiology by the release of several molecules including neurotrophins and cytokines. Recently, extracellular vesicles (EVs) have been considered as key players in the development and progression of chronic and degenerative diseases. An alteration of the homeostatic state of peripheral cells is reflected on the molecular cargo of EVs which, in turn, can affect the functioning of the neurons. Common to several chronic and neurodegenerative diseases, there is a reduction of peripheral innervation which leads to a disturbance of the trophic relation between the body and the central nervous system. A continuous alteration of these interactions during maturity of individuals may underlie some of the early events that reflect on neuronal death during aging. CNS, central nervous system; EVs, extracellular vesicles; PNS, peripheral nervous system.