β-Amyloid_1–42Induces Neuronal Death through the p75 Neurotrophin Receptor

Abstract

Alzheimer's disease is characterized by the accumulation of neurotoxic amyloidogenic peptide A␤, degeneration of the cholinergic innervation to the hippocampus (the septohippocampal pathway), and progressive impairment of cognitive function, particularly memory. A␤ is a ligand for the p75 neurotrophin receptor (p75 NTR ), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimer's disease. Here we examined whether p75 NTR is required for A␤-mediated effects. Treatment of wild-type but not p75 NTR -deficient embryonic mouse hippocampal neurons with human A␤ 1-42 peptide induced significant cell death. Furthermore, injection of A␤ 1-42 into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75 NTR -deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to A␤-induced toxicity. We also found that neuronal death correlated with A␤ 1-42 peptide-stimulated accumulation of the death-inducing p75 NTR C-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75 NTR . Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor-␣ protease inhibitor-2), A␤ 1-42 -induced accumulation of the C-terminal fragment resulted from inhibition of ␥-secretase activity. These results provide a novel mechanism to explain the early and characteristic loss of cholinergic neurons in the septohippocampal pathway that occurs in Alzheimer's disease.

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

“…Relevantly, as previously reported and as shown in Fig. S3b, Abeta exposure induces an overload of p75 CTF, but not of p75 ICD fragments, probably because of an inhibition of ␥ secretase activity (17). In contrast, in NGF-deprived neurons the accumulation of Abeta (5) and of p75 ICD fragments ( Fig.…”

“…The finding that these events can also be induced by Abeta extracellular exposure confirms the primary role attributed to Abeta in this hypothesis. However, the fact that in its intracellular produced form due to NGF withdrawal Abeta is capable of inducing changes different from those reported when externally added (17), and at concentrations that are an order of magnitude lower than those necessary to cause analogous cellular events when exogenously added, suggests that its toxic action may involve some intracellular players such as, for instance, NGF receptors, via their anomalous activation or processing.…”

“…An Abeta pathway, inducing TrkA phosphorylation directly by itself and indirectly by promoting NGF secretion (28), has recently been reported. p75 expression is also linked to changes occurring in AD (17,29), probably through its direct binding to Abeta 1-42 peptides (29,30). In addition, p75 mediates APP promoter activity, leading to an increase of secreted APP (31,32), and undergoes intramembrane ␣ and ␥ secretase-mediated processing to generate p75 CTF and p75 ICD fragments, respectively (11).…”

“…It was also recently demonstrated that p75 may mediate the Abeta 1-42 neuronal death mechanism via its processing (17) to produce p75 C-terminal fragment (CTF). To evaluate whether p75 processing also occurs in NGF-deprived neurons, we have performed Western blot analysis of these fragments in cytosolic and nuclear compartments.…”

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

“…In addition, the fact that partial TrkA and p75 silencing or the inhibition of aberrant TrkA phosphorylation, prevents neuronal death and Ab production, suggests that this cooperation may also occur in a nonphysiological fashion in NGF deprived hippocampal neurons, by activating a prodeath signal. To support this conclusion, p75-silenced hippocampal neurons exposed to Ab peptides do not die and p75 processing is blocked (Sotthibundhu et al, 2008). Moreover, AD12 mouse, obtained by crossing AD11 mouse (Capsoni et al, 2002a,b) with the p75 ExonIII knockout mouse (Lee et al, 1992), does not show Ab accumulation .…”