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

Abstract

Soluble oligomeric forms of amyloid beta (Aβ) play an important role in causing the cognitive deficits in Alzheimer's disease (AD) by targeting and disrupting synaptic pathways. Thus, the present research is directed toward identifying the neuronal pathways targeted by soluble forms and, accordingly, develops alternative therapeutic strategies. The neurotrophin brain-derived neurotrophic factor (BDNF) is synthesized as a precursor (pro-BDNF) which is cleaved extracellularly by plasmin to release the mature form. The conversion from pro-BDNF to BDNF is an important process that regulates neuronal activity and memory processes. Plasmin-dependent maturation of BDNF in the brain is regulated by plasminogen activator inhibitor-1 (PAI-1), the natural inhibitor of tissue-type plasminogen activator (tPA). Therefore, tPA/PAI-1 system represents an important regulator of extracellular BDNF/pro-BDNF ratio. In this review, we summarize the data on the components of the plasminogen activation system and on BDNF in AD. Moreover, we will hypothesize a possible pathogenic mechanism caused by soluble Aβ forms based on the effects on tPA/PAI-1 system and on the consequence of an altered conversion from pro-BDNF to the mature BDNF in the brain of AD patients. Translation into clinic may include a better characterization of the disease stage and future direction on therapeutic targets.

Keywords: Alzheimer’s disease; amyloid beta; brain-derived neurotrophic factor; plasminogen activator inhibitor-1; tissue-type plasminogen activator.

Figure 1

Relationship between plasminogen activation system and BDNF at the synaptic level. tPA and PAI‐1 may be released into the extracellular space where plasminogen is also present. tPA can influence synaptic activity by two ways: (1) by binding directly to specific subunits of NMDA receptors and (2) by increasing the levels of plasmin, which in turn leads to increased BDNF maturation and increased synaptic activity (LTP) after binding with the TrkB receptor. PAI‐1 inhibits tPA activity, thus reducing the synthesis of plasmin and the maturation of BDNF. In the context of Alzheimer‘s disease, elevated PAI‐1 levels may account for increased Aβ accumulation and increased pro‐BDNF, which reduces synaptic function (LTD) after binding with the p75 receptor. Long‐term consequences may include cognitive deficits and fostering of neurodegenerative processes

Figure 2

Putative scheme of pathogenic mechanism of amyloid beta soluble forms in AD through tPA/PAI‐1 and BDNF. By upregulating PAI‐1, Aβ soluble forms inhibit tPA and plasmin synthesis. This mechanism impairs the extracellular conversion from pro‐BDNF to the mature BDNF. An altered ratio of pro‐BDNF/BDNF in favor of the pro‐form may lead to an enhancement of LTD and reduction of LTP in hippocampal neurons, with consequent synaptic dysfunction and memory deficits. In addition, a long‐lasting reduction of mature BDNF may contribute to neuronal atrophy and death. Aβ: amyloid beta; BDNF: brain‐derived neurotrophic factor; PAI‐1: plasminogen‐activator inhibitor‐1; tPA: tissue plasminogen‐activator