Alzheimer's disease is now increasingly associated with the dysfunction of microglia. Generally speaking, microglia are originally supposed to protect the brain - they clear amyloid -β (Aβ) and also protect synapses. However, when they are ill, they may instead spread Aβ through exosomes and even over-trim synapses through the complement system, causing losses. In this way, microglia play A dual role: they are both the "scavengers" of Aβ and may also be its "disseminators". Recent studies have found that the role of the molecule BACE-1 in microglia is also rather contradictory. If it is removed, it can indeed enhance the clearance of Aβ, which seems like a good thing. But here comes the problem - after the deletion of BACE-1, the cell's energy metabolism will shift towards glycolysis and also activate a lactic acid-dependent Kv1.3 channel. As A result, a metabolic change makes it easier for Aβ to be released through exosomes, accelerating synaptic degeneration. This contradictory phenomenon might explain why so many inhibitors targeting BACE-1 keep failing in clinical trials. Some people have suggested that BACE-1 might act like a "metabolic switch", determining whether microglia protect or damage the brain. So, perhaps we shouldn't directly target BACE-1, but rather control the Kv1.3 channel downstream of it. Inhibiting Kv1.3 can not only block the release of Aβ exosomes caused by lactic acid, but also will not affect the cleaning effect brought by the inhibition of BACE-1. If these two strategies are combined, controlling metabolism on the one hand and inhibiting proteins on the other, it might be possible to deal with the accumulation and spread of Aβ in Alzheimer's disease more effectively.

Wei Wang. Microglia BACE-1 as a Metabolic Switch Driving Lactate-Kv1.3-Exosome-Mediated Propagation in Alzheimer's Disease. Academic Journal of Agriculture & Life Sciences (2026), Vol. 7, Issue 1: 1-9. https://doi.org/10.25236/AJALS.2026.070101.

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