What lysosomal pH range optimizes pathological seed degradation without generating toxic fragments?

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Description

The debate identified lysosomal pH modulation as promising but didn’t establish the therapeutic window between effective clearance and harmful fragment generation. This narrow optimization range is critical for safety.

Source: Debate session sess_SDA-2026-04-08-gap-pubmed-20260406-062207-b800e5d3 (Analysis: SDA-2026-04-08-gap-pubmed-20260406-062207-b800e5d3)

Resolution criteria

Resolution requires: (1) pH-dose-response curves for lysosomal processing of pathological tau seeds in primary neurons, measuring both degradation products (SDS-stable fragments) and residual seeds (ThT fluorescence) across pH range 4.0-6.5; (2) identification of the pH threshold where seed degradation drops below 50% while toxic fragment generation exceeds baseline by >=30%; (3) in vivo validation in tau P301S mice using per os or intrahippocampal administration of pH-modulating compounds (chloroquine, NH4Cl), showing therapeutic window where pathology is reduced by >=40% without behavioral toxicity. Cell-free assays alone cannot establish the therapeutic window for in vivo translation.

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