Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer's neuropathology and cognitive deficits

Abstract

Brain-derived neurotrophic factor (BDNF) plays pivotal roles in neuronal function. The cleaved - mature - form of BDNF (mBDNF), predominantly expressed in adult brains, critically determines its effects. However, insufficient proteolytic processing under pathology may lead to the precursor form of BDNF (proBDNF) and thereby increased neuronal apoptosis and synaptic weakening. Previous findings in our lab showed that cognitive stimulation (CS) delayed memory decline in Tg2576 mouse model of Alzheimer's disease (AD), an effect that was tightly associated with augmented levels of mBDNF. In view of this association, the present study explored whether altered cleavage of BDNF could be involved in AD-related traits triggered by excessive amyloid-β (Aβ) pathology and whether this process could be therapeutically targeted. Aβ pathology, both in AD patient samples and experimental models, triggered the upregulation of plasminogen-activator inhibitor-1 (PAI-1) via JNK/c-Jun. This led to inhibition of plasmin-regulated conversion of mBDNF. Pharmacological inhibition of PAI-1 with PAI-039 sufficiently reverted Aβ-induced tau hyperphosphorylation and neurotoxicity. Chronic treatment of 15 old-month Tg2576 mice with oral administration of PAI-039 resulted in improved BDNF maturation and cognitive function without inducing significant changes in amyloid burden. In conclusion, upregulation of PAI-1 may be a critical mechanism underlying insufficient neurotrophic support and increased neurodegeneration associated with AD. Thus, targeting BDNF maturation through pharmacological inhibition of PAI-1 might become a potential treatment for AD.

Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease: Consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications

“…The data exposed above suggest that one of the possible mechanisms by which soluble Aβ forms affect synaptic function is linked to the changes observed in the tPA/PAI-1 system and, consequently, to the effects on pro-BDNF/BDNF ratio (Figure 1). Supporting this hypothesis, a recent study 54 with a mouse genetic model of familial AD (Tg2576) and post-mortem brain tissues has shown that Aβ soluble forms might impair BDNF proteolytic processing through modulation of neuronal PAI-1.…”

“…Injection of Aβ 1‐40 into CA1 region of the hippocampus of mice lacking tPA or plasminogen causes a strong PAI‐1 accumulation but not in the wild type. In addition, primary cortico‐hippocampal cultures from mouse AD model (Tg2576) cultured in the presence of the pathogenic fragment Aβ25‐35 immediately show a dramatic increase in PAI‐1 synthesis through activation of JNK‐dependent c‐Jun pathways …”

“…53 Furthermore, it has been shown that direct injection of Aβ into brain regions may cause an increase of PAI-1. Injection of Aβ 54 through activation of JNK-dependent c-Jun pathways. 55,56 Altogether these data indicate that the changes in the expression of plasminogen activators and inhibitors may occur during AD course and account, at least in part, for Aβ accumulation and lack of degradation.…”

“…66,111 In addition, investigation of proteins involved in synaptic regulation and neuronal survival, such as BDNF and the related proteins to cross the blood-brain barrier and to deliver the right amount of trophic factor in the target region. Instead, the tPA/PAI-1 pathway can be targeted by pharmacological agents, 54 a strategy that has been already adopted in other types of diseases such as diabetic nephropathy 114 and fibrosis. 115 However, there is a need to explore the effects of these agents on BDNF expression in healthy and AD subjects.…”

Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis

“…BDNF has been implicated in the modulation of energy balance [10], as alterations in its expression levels and activities result in a number of neurodegenerative disorders, covering Huntington disease, Alzheimer disease and Parkinson disease [11] ; [12]. Heretofore, it was not yet identified whether abdominal radiotherapy influenced BDNF expression in the brain.…”