A newly published Perspective article in Progress in Neurobiology by Bhavna Verma (DPAG), Preman Singh (DPAG and Dallas VA Medical Center), Deborah Goberdhan (NDWRH) and Clive Wilson (DPAG) has highlighted recent evidence supporting a new model by which β-amyloid, a key player in Alzheimer’s Disease, might trigger the first pathological events in neurodegeneration. They have made several contributions to studies, which suggest that the regulated secretory pathway is involved. Regulated secretion mediates the release of signals, such as neuropeptides, in a controlled fashion. This secretory system has a quality control pathway, which normally appears to generate low levels of Aβ that are destroyed by lysosomes, the cell’s waste disposal organelles. If Aβ starts to accumulate, there is increased flow into this pathway, but trafficking to the lysosome stalls. This promotes more Aβ generation and a so-called endolysosomal trafficking defect, which is propagated abnormally to other cells, mirroring defects observed in early Alzheimer’s Disease patients.
Bhavna Verma, who undertook key studies leading to this review, commented: ‘More recently, we have found that overexpressing tau, a microtubule-associated cytoskeleton regulator that forms neurofibrillary tangles in Alzheimer’s, also selectively interferes with early events in regulated secretion, generating endolysosomal defects. We believe that there is a cross-talk between maturation of regulated secretory compartments and the microtubule cytoskeleton, which involves the microfilament cytoskeleton and have identified some of the mediators of these interactions. The mechanisms involved may highlight new target pathways for therapies, and shift the focus from trying to stimulate more lysosomal degradation in patients to suppressing the initial formation of aberrant compartments that cannot be degraded efficiently.’
You can read more about how this new model helps to explain several recent observations relating to Alzheimer’s pathology in Verma, B. et al. (2026) Defective Regulated Secretion: A Trigger for Alzheimer’s Pathology?, Prog. Neurobiol. 262, 102926.[KW1]