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Figure 2: The Aβ peptides accumulating in the early stages of AD also stimulate cilial p75NTR like the neuro-trophins and with this the proliferation of granule cell progenitors and their TA progeny. But the additional neurogenesis expected from this stimulation fails and neurogenesis drops because proNGF can no longer be converted into mature NGF because of a developing shortage of plasmin resulting from an Aβ1-42-induced fall in tPA. But proNGF preferentially binds and activates the p75NTR•sortilin complexes instead of NGF•TrkA complexes on the BFCSN axons. The retrograde flow of p75NTR•sortilin signals down the axons kills the BFCSNs and stops the hippocampal supply of ACh that would otherwise promote the survival of the TA precursor neurons. Furthermore, TA neurons that do survive are prevented from further maturing by the lack of SST?a hallmark of the AD brain?and the consequent silencing of SSTR3 signaling.
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