Cognitive Dysfunction
The classic MAPK cascade involves activation of the small GTPase Ras, and the kinases Raf and MEK [86,87]. Downstream consequences of MAPK activation include activation of the ribosomal S6 kinases (Rsk) and the MAPK-activated protein kinase 2 (MAPKAP2), which phosphorylates several transcription factors including Elk-1 and cAMP-regulated response element binding protein (CREB) [85]. The physiological significance of this elaborate NGF-induced network remains unclear, but the sustained activation of MAPK is linked to neurotrophin-mediated neurite outgrowth [88,89] PubMed:18986241
Since the cholinergic deficit is not an early defect in the progression of AD [18–20], the use of these drugs in the prodromal stages of AD should be continued. However, the limited effect of cholinesterase inhibitors for the treatment of cognitive decline in AD coupled with unwanted side effects such as diarrhea, nausea, insomnia, fatigue and loss of appetite indicates the need to move beyond this conventional drug treatment with somewhat circumscribed efficacy. PubMed:18986241
In this regard, AChE has been localized to SPs in the vicinity of cholinergic synapses, and experimental evidence suggests that AChE promotes Ab fibrillization [164], suggesting that a further benefit from AChE inhibitor therapy may be to prevent continued Ab deposition in cholinergic projection sites. PubMed:18986241
Significantly, while we have shown that reduced TrkA levels in the cortex were positively associated with lower cognitive performance as assessed by Mini-Mental State Exam (MMSE) test scores [64], increased cortical proNGF levels were negatively correlated with MMSE performance [61]. PubMed:18986241
A second downstream pathway is the PI3K/Akt pathway that regulates neurotrophin-mediated survival responses in PC12 cells [90,91]. Regulation of this pathway involves upstream elements including Ras/Gab1/IRS1 [92,93]. PubMed:18986241
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