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

Summary 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.

Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus

“…A direct consequence of the glymphatic system disturbance is the reduced clearance of neurotoxic substances, such as beta amyloid (Aβ) and hyperphosphorylated tau (HP tau) 53,87 . Accumulation of these neurotoxic substances could not only impair physiological functions of neurons, but also trigger astrogliosis and neuroinflammation 96 . Several studies reported the aggregation of Aβ and HP tau in brain biopsy samples from iNPH patients 97 .…”

“…DTI‐MRI is another useful technique to assess the white matter lesion. Mean diffusivity (MD) and fractional anisotropy (FA) are two commonly analyzed DTI parameters 96 . MD increases when more free water diffuses in the extracellular space.…”

Spinosin Attenuates Alzheimer’s Disease-Associated Synaptic Dysfunction via Regulation of Plasmin Activity

“…The tissue plasminogen activator (tPA)/plasmin system has been suggested as a therapeutic target for AD (Angelucci et al, 2019). Plasmin can cleave Aβ and Aβ deposits, suggesting that it may be involved in Aβ clearance (Ledesma et al, 2000;Jacobsen et al, 2008;Baranello et al, 2015).…”

The recent development in synthesis and pharmacological evaluation of small molecule to treat Alzheimer's diseases: A review

“…Among these compounds, (E)-5-(4hydroxystyryl) quinoline-8-ol showed the most potent ability to inhibit selfinduced Aβ aggregation (IC50 = 8.50 μM) and copper(II)-induced Aβ aggregation and to disassemble the well-structured Aβ fibrils generated by self-and copper(II)-induced Aβ aggregation ( Figure 2) (Mao et al, 2014b). Previously it has been shown that molecular deletion of plasminogen activator inhibitor 1 PAI-1 significantly reduced brain Aβ load in animal model (Angelucci et al, 2019). In this regard, oral administration of TM5275, a small molecule inhibitor of PAI-1, has been indicated to reduce A β load in the hippocampus and consequently improve memory function in animal model (Akhter et al, 2018).…”