proBDNF is modified by advanced glycation end products in Alzheimer’s disease and causes neuronal apoptosis by inducing p75 neurotrophin receptor processing

Abstract

Alzheimer disease (AD) is a complex pathology related to multiple causes including oxidative stress. Brain-derived neurotrophic factor (BDNF) is a neutrotrophic factor essential for the survival and differentiation of neurons and is considered a key target in the pathophysiology of various neurodegenerative diseases, as for example AD. Contrarily to BDNF, the precursor form of BDNF (proBDNF) induces apoptosis through the specific interaction with p75 and its co-receptor, Sortilin.We used hippocampal tissue and cerebrospinal fluid from AD patients and controls. to study the localization and the levels of proBDNF, p75 and Sortilin as well as the post-traduccional modifications of proBDNF induced by Radical Oxygen Species, by immunofluorescence and Western blot. Differentiation and survival were assessed on differentiated mouse hippocampal neurons derived from postnatal neural stem cells from WT animals or from the transgenic AD animal model APP/PS1∆E9, based on mutations of familiar AD. In AD patients we observe a significative increase of proBDNF and Sortilin expression and a significative increase of the ratio proBDNF/BDNF in their cerebrospinal fluid compared to controls. In addition, the proBDNF of AD patients is modified by ROS-derived advanced glycation end products, which prevent the processing of the proBDNF to the mature BDNF, leading to an increase of pathogenicity and a decrease of trophic effects. The cerebrospinal fluid from AD patients, but not from controls, induces apoptosis in differentiated hippocampal neurons mainly by the action of AGE-modified proBDNF present in the cerebrospinal fluid of the patients. This effect is triggered by the activation and processing of p75 that stimulate the internalization of the intracellular domain (ICD) within the nucleus causing apoptosis. Induction of apoptosis and p75 ICD internalization by AD patients-derived proBDNF is further enhanced in neuron cultures from the AD model expressing the APP/PS1∆E9 transgene.Our results indicate the importance of proBDNF neurotoxic signaling in AD pathology essentially by three mechanisms: i) by an increase of proBDNF stability due to ROS-induced post-traductional modifications; ii) by the increase of expression of the p75 co-receptor, Sortilin and iii) by the increase of the basal levels of p75 processing found in AD.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0411-6) contains supplementary material, which is available to authorized users.

Receptor for Advanced Glycation End Products Acts as a Fuel to Colorectal Cancer Development

“…Many studies have demonstrated AGEs are considered as potent toxic molecules that produce several non-communicable diseases such as T2D, CRC, cardiovascular diseases, Parkinson disease, AD (63)(64)(65)(66)(67)(68). Epidemiological evidence has reported that elevated AGEs were associated with CRC (69).…”

Comparative studies of glial fibrillary acidic protein and brain‐derived neurotrophic factor expression in two transgenic mouse models of Alzheimer’s disease

“…Earlier studies found significantly reduced levels of both proBDNF and BDNF in parietal cortex taken from subjects with mild cognitive impairment and mild to moderate AD compared with age‐matched controls 21 . However, recent work has reported that proBDNF levels in the hippocampus as well as CSF proBDNF/BDNF ratios were both significantly higher in AD subjects compared with age‐matched controls, and also found evidence supporting a role for proBDNF‐p75/Sortilin signalling in AD pathogenesis 47 …”

Serum BDNF Levels Are Reduced in Patients with Disorders of Consciousness and Are Not Modified by Verticalization with Robot-Assisted Lower-Limb Training

“…Although mature BDNF promotes neurogenesis and activates prosurvival signaling through tropomyosin receptor kinases (Trks) [23][24][25], its precursor proBDNF binds to the p75 neurotrophin receptor (p75NTR), a tumor necrosis factor receptor-like molecule. Activation of p75NTR by proBDNF can induce neuronal apoptosis in different conditions [26][27][28]. p75NTR is expressed widely during synaptogenesis and subsequently downregulated in the adult brain.…”