Researchers at this institution are delving into cellular dysfunction that may be present in the initial stages of Alzheimer’s disease, before the onset of misfolded amyloid-β accumulation and cognitive decline. Addressing the disease early on is always more feasible if the right target is identified. The main challenge lies in pinpointing and comprehending the causative mechanisms, especially when access to brain tissue is limited in the early stages of Alzheimer’s and existing animal models may not fully emulate the human condition.
Amyloid precursor protein (APP) resides in the cell membranes of brain cells, continually generating new molecules while breaking down old ones. Enzymatic processes involving gamma-secretase eventually lead to the production of amyloid-β (Aβ) peptides in Alzheimer’s disease. Initially, inhibiting gamma-secretase was considered a logical approach to halt the production of toxic Aβ fragments. However, this results in the accumulation of APP-C-Terminal Fragments (APP-CTFs) which are also detrimental to neurons. These fragments disrupt the calcium balance within lysosomes, key components for degrading cellular waste, leading to an imbalance that impacts overall neuron health. This disturbance in the endolysosomal system appears to be linked to early AD pathology, shedding new light on the disease process.
These findings offer valuable insights into potential disease triggers in early AD stages, suggesting that fragments of the APP molecule, rather than Aβ, may play a significant role. This challenges current therapeutic strategies focused on clearing amyloid plaques and underscores the importance of early intervention in tackling AD. Understanding these mechanisms could pave the way for more effective treatments.
Link: https://press.vib.be/new-mechanism-uncovered-in-early-stages-of-alzheimers-disease
