Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats
Figure 1
Proposed mechanism of pro-NGF induced neurodegeneration in Alzheimer’s disease and age-matched controls. (1) The cleavage of plasminogen to plasmin is altered due to decreased tPA from increased PAI-1 activity, leading to an accumulation of pro-NGF in the hippocampus. (2) Increased pro-NGF leads to a preferential activation of the high affinity p75NTR/sortilin complex. (3) As NGF is down-regulated and pro-NGF is upregulated, high affinity NGF binding to TrkA receptors is compromised. (4) There is a shift in the balance of TrkA and p75NTR at the distal axon of the BFCN. (5) Pro-NGF/p75NTR/sortilin signaling increases JNK signaling and ultimately induces degeneration of the BFCNs. In age-matched controls (normal aging), balanced tPA activity allows for (1) cleavage of pro-NGF to yield NGF and (2) sustained NGF/TrkA signaling to promote cholinergic integrity. Abbreviations: tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), nerve growth factor (NGF), tropomyosin related kinase A (trkA = high affinity NGF receptor), pan neurotrophin receptor p75NTR (p75NTR = high affinity pro-NGF receptor).
