Selective vulnerability in Alzheimer's disease: Amyloid precursor protein and p75^NTR interaction

Abstract

Objective-Selective neuronal vulnerability in neurodegenerative diseases is poorly understood. In Alzheimer's disease, the basal forebrain cholinergic neurons are selectively vulnerable, putatively because of their expression of the cell death mediator p75 NTR (the common neurotrophin receptor), and its interaction with proapoptotic ligands pro-nerve growth factor and amyloid-β peptide. However, the relation between amyloid precursor protein (APP) and p75 NTR has not been described previously.Methods-APP and p75 NTR were assayed for interaction by coimmunoprecipitation in vitro and in vivo, yeast two-hybrid assay, bioluminescence resonance energy transfer, and confocal microscopy. Effects on APP processing and signaling were studied using immunoblotting, enzyme-linked immunosorbent assays, and luciferase reporter assays.Results-The results of this study are as follows: (1) p75 NTR and APP interact directly; (2) this interaction is modified by ligands nerve growth factor and β-amyloid; (3) APP and p75 NTR colocalization in vivo is modified in Alzheimer's model transgenic mice; (4) APP processing is altered by p75 NTR , and to a lesser extent, p75 NTR processing is altered by the presence of APP; (5) APP-dependent transcription mediated by Fe65 is blocked by p75 NTR ; and (6) coexpression of APP and p75 NTR triggers cell death.Interpretation-These results provide new insight into the emerging signaling network that mediates the Alzheimer's phenotype and into the mechanism of basal forebrain cholinergic neuronal selective vulnerability. In addition, the results argue that the interaction between APP and p75 NTR may represent a therapeutic target in Alzheimer's disease.The common neurotrophin receptor, p75 NTR , has been implicated as a potential mediator of Alzheimer's disease pathogenesis in several different ways. First, p75 NTR expression is highly restricted in the adult nervous system, and its main site of expression, the basal forebrain cholinergic neurons, represents a selectively vulnerable region in Alzheimer's disease. [1][2][3] Second, p75 NTR mediates programmed cell death, 4-7 and the expression of p75 NTR sensitizes cells to β-amyloid (Aβ) toxicity. 8 Third, Aβ has been shown to interact directly with p75 NTR,9 and this interaction may lead to apoptosis induction. 9 These studies suggest that one mechanism by which p75 NTR may participate in Alzheimer's disease pathogenesis is by binding Aβ peptide and triggering programmed cell death. However, recent studies suggest that Aβ peptide also binds to its parent, APP (β-amyloid precursor protein), multimerizing APP, inducing caspase cleavage of APP intracytoplasmically at Asp664, and inducing programmed cell death. 14,15 Furthermore, the Aβ-induced cleavage of APP at Asp664 may play a key role in nonapoptotic features of the Alzheimer's phenotype, such as hippocampal synapse loss, dentate gyral atrophy, and reduction in excitatory postsynaptic potentials at CA1 after stimulation of the Schaeffer collaterals of CA3 neurons, because the addition of a...

Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging

“…The candidate receptors where direct protein binding of APP or APP fragments has been demonstrated in vitro are the death receptor DR6 (coupling the N-terminal APP fragment N-APP to apoptosis) (Nikolaev et al 2009), p75 and Integrin-b1 (Young-Pearse et al 2008;Kim and Tsai 2009;Nikolaev et al 2009) (Fombonne et al 2009). Despite a lack of evidence for direct protein binding, sAPPa-mediated neuroprotection may also require expression of the insulin receptor (IR) (Jimenez et al 2011).…”

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

“…TrkA and TrkB activation imparts neuroprotection to the RGCs in experimental models of glaucoma [5,65,66] and Ab binding to TrkB-FL receptor negatively affects the synaptic plasticity [67]. Ab binding to the p75NTR has similarly been demonstrated to induce apoptosis and p75NTR One protein, multiple pathologies: multifaceted involvement of amyloid b in… suppression protected RGCs following ON injury indicating potential pathological roles of Ab in the retina [65,68].…”

The Effects of Transmembrane Sequence and Dimerization on Cleavage of the p75 Neurotrophin Receptor by γ-Secretase

“…Whether these influences are primarily due to physical interaction (herein), activation of secretases (9,11), and/or movements within membrane compartments (7) remains to be determined. Other heterodimer interactions might also alter the rate of ␥-secretase cleavage, and impact on the ability of p75 NTR to signal (36,53), because they modulate the p75 NTR transmembrane structure. Further investigation of the effect of proteins that can associate with p75 NTR and modulate RIP are therefore warranted.…”