First, the BDNF is translated as a precursor form and then processed by the intracellular/extracellular proteases into mature BDNF (mBDNF). Transformation of proBDNF into mBDNF is a critical step to regulate the mBDNF/TrkB signaling because proBDNF preferentially binds with p75/sortilin receptor but not with TrkB. In addition, contrarily to the positive influence of mBDNF on CNS neurons, proBDNF induces synaptic depression and apoptosis via p75/sortilin signaling
[33][34]. In hippocampal tissue and CSF from AD patients, the expression of proBDNF, sortilin, and the ratio of proBDNF/BDNF were increased in comparison with healthy controls
[9]. proBDNF in AD patients was highly modified with advanced glycation end products which prevents proteolytic cleavage by proteases. Administration of CSF from AD patients caused apoptosis in the primary culture of hippocampal neurons via p75/sortilin receptor-dependent manner. In addition to post-translational modification in the BDNF protein, the alternation of protease activity also influences the BDNF processing. Proteolytic cleavage of proBDNF into mBDNF was regulated by intracellular and extracellular proteases including mammalian Kexin-like proteases (Furin, PC 1/3/7), tissue plasminogen activator (tPA)/plasmin system (plasminogen, plasmin, tPA, plasminogen activator inihibitor-1 (PAI-1), and alpha (2)-antiplasmin), and matrix metallopeptidases 9 (MMP9)
[33]. Interestingly, tPA/the plasmin system and MMP9 also cleave and degrade Aβ peptide. Therefore, activity of these proteases may impact both Aβ accumulation and mBDNF expression. In the neocortex of AD patients, the levels of plasminogen (pro-type of plasmin) and plasmin were lower than healthy controls
[35]. Cai et al. reported that AD model mice showed a lower plasmin level in the hippocampus
[36]. They also found that a treatment of spinosyn, a flavonoid isolated from Zizyphus jujuba var spinosa seeds, increased expression and activity of hippocampal plasmin and synaptic plasticity in AD model mice. The beneficial effect of spinosyn on synaptic plasticity was blocked by a plasmin inhibitor. Activity of tPA, an endogenous activator of plasmin, is also downregulated in the AD brain in accordance with an increased expression of neuroserpin, an endogenous inhibitor of tPA
[37]. In addition, an upregulation of PAI-1, another endogenous inhibitor of tPA, was also reported in Aβ-treated primary neurons, the hippocampus of AD model mice and frontal cortex of AD patients
[38]. Aβ peptide induced PAI-1 upregulation through the JNK/c-Jun pathways. The PAI-1 inhibitor resulted in improved BDNF maturation and cognitive function without affecting the burden level of amyloid. Further, cognitive stimulation given at a pre-plaque and pre-symptomatic phase protected from cognitive decline in accordance with an increase of PAI-1, decreased activity of tPA, and enhanced production of mBDNF in AD model mice. On the other hand, neuronal overexpression of MMP-9 in AD model mice resulted in increased soluble amyloid precursor protein α(sAPPα) levels, decreased Aβ oligomers, enhanced insulin signaling, and increased mBDNF levels, and prevented the cognitive deficits
[39]. Hu et al. showed that PL402, rhamnoside derivative, suppressed the Aβ level via upregulation of MMP3/9 in cell models
[40]. PL402 also attenuated Aβ pathology and cognitive defects in AD model mice with the consistent increase of MMP3/9. MMP9 also has a role in leukocyte migration from circulation into the brain under inflammatory conditions
[41]. Indeed, knockout of MMP2 and MMP9 showed neuroprotective effects against inflammation in a murine model of experimental autoimmune encephalomyelitis
[42][43]. Considering that neuroinflammation is one of the major pathologies of AD, it is required to carefully assess the possible impact of a protease enhancer on neuroinflammation. Collectively, enhancement of the BDNF and Aβ processing via proteases is a potential therapeutic strategy in AD, while it is required to take into account side effects.