The authors of this open access paper provide an overview of two viewpoints on the onset and progression of neurodegenerative conditions. The biochemistry of the brain is exceptionally complex, and its dysfunction is also complex. It is clear that the aggregation of a few forms of altered protein is important in neurodegeneration, but exactly how and why it is important remains an active area of research. There are points of consensus, points of debate, and this landscape shifts over time as new evidence emerges. The absence of curative therapies for neurodegenerative conditions is a symptom of the inability to determine the critical mechanisms driving dysfunction, distinguishing them from the many interacting consequences of those mechanisms and other changes associated with degenerative aging.
Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneering researchers have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases.
The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation.
Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.
Link: https://doi.org/10.3389/fnagi.2024.1370580
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