An Emphasis on Impaired Neurogenesis as an Early Stage of Alzheimer's Disease

There is a diversity of thought regarding the mechanisms of Alzheimer's disease, even if it may seem that the vast majority of funding and attention is focused on protein aggregation, whether amyloid-β or tau. There was a great deal of alternative theorizing during the long years in which amyloid-β clearance was failing, and that has given rise to numerous research and development programs focused on inflammatory signaling or other mechanisms that might be relevant to neurodegenerative pathology. The theorizing continues apace, even now that amyloid-β clearance is starting to show some signs of working, at least in the early stages of Alzheimer's disease. The paper here is an example of the type, seeking to draw attention away from protein aggregates and toward other aspects of the complex biology of the aging brain.

Despite the wealth of new insights into the dysregulated processes underlying the appearance of toxic amyloid plaques and hyperphosphorylated tau protein, treatments targeting these continue to fail to cure Alzheimer's disease (AD), and offer only minimal symptomatic relief. This raises a pivotal question: have we thoroughly explored the classic amyloid and tau hypotheses with no causative mechanism identified, signalling a need for a paradigm shift? Furthermore, the current affinity among researchers to view new evidence solely through the lens of the well-established amyloid and tau hypotheses could be hindering the exploration of other genes and proteins and their multifaceted roles within the human brain as potential initiators and drivers of AD pathology.

Perhaps it is time to consider a novel perspective on AD, emphasizing impaired neurogenesis as an early aetiological factor. In this review, we explore the existing knowledge of adult hippocampal neurogenesis (AHN) and extend our inquiry into the perspective that compromised AHN could serve as a fundamental player in the prodromal and preclinical phases of AD, even preceding the amyloid and tau features. We aim to unravel the molecular interplay underlying impaired AHN, thus contributing to a deeper understanding of the complex landscape of AD pathogenesis.

A novel hypothesis is presented, interweaving the roles of Notch signalling and heparan sulfate proteoglycans (HSPGs) in compromised AHN. While acknowledging the significance of the amyloid and tau hypotheses, it calls for further exploration beyond these paradigms, suggesting the potential of altered heparan sulfate (HS) sulfation patterns in AD initiation. Future directions propose more detailed investigations into early HS aggregation, aberrant sulfation patterns, and examination of their temporal relationship with tau hyperphosphorylation. In challenging the conventional 'triggers' of AD and urging their reconsideration as symptoms, this review advocates an alternative approach to understanding this disease, offering new avenues of investigation into the intricacies of AD pathogenesis.


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