BDNF RECEPTOR DYSREGULATION IN ALZHEIMER'S-DISEASE: EXTRACELLULAR VESICLE-MEDIATED TRANSPORT OF A SYNAPTOTOXIC TRKB FRAGMENT

The neuroprotective BDNF/TrkB-FL system is compromised in Alzheimer’s disease (AD). Amyloid-beta triggers calpain-mediated TrkB-FL receptor cleavage, leading to TrkB-ICD formation, a novel intracellular fragment. Biological fluids are used to pinpoint potential disease biomarkers and extracellular vesicles (EVs) are cell-specific carriers of promising pathological biomarkers. Thus, this work aimed to 1) investigate TrkB-ICD effects and 2) its presence in AD human samples and EVs. To that endeavour, neurons were transduced with either LV-CamKII-GFP or LV-CamKII-TrkB-ICD-IRES-ZsGreen and used for patch clamp, dendritic spine and transcriptomic analysis. For CSF and plasma samples, patients fulfilled the criteria for Mild Cognitive Impairment due to AD (MCI_AD), whereas controls (MCI_CONTROL) reported cognitive complaints but had no evidence of Aβ pathology or neuronal injury. MCI_AD plasma-derived EVs (pdEVs) were isolated using the ExoQuick reagent and characterized. Neurons overexpressing TrkB-ICD were enriched in phosphotyrosine proteins (p=7.62x10-3,n=3) and possessed fewer dendritic spines (p=1.15x10-10, n=13-15 cells/3 cultures). TrkB-ICD neurons are also more hyperexcitable given by mEPSC increase (p=2.46x10-2, n=7-8 cells/3cultures) and concomitant decrease in resting membrane potential (p=1.26x10-2, n=7-8 cells/3 cultures). Transcriptomic data revealed that TrkB-ICD upregulates 23 GO terms, encompassing genes implicated in for synaptic structure/function. CSF analysis showed not only an increase in TrkB-ICD immunoreactivity in MCI due to AD patients (p=7.55x10-3,n=23-46), but also a negative correlation between the levels of Aβ1-42 and TrkB-ICD (ρ=-0.47, n=46). PDEVs of MCI_AD patients contained higher levels of TrkB-ICD (p=0.010, n=17-18). Collectively, these findings indicate that TrkB-ICD is secreted extracellularly, suggesting a possible mechanism for the dissemination of its toxic effects.