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Vasefi et al. Vessel Plus 2020;4:24 I http://dx.doi.org/10.20517/2574-1209.2020.16 Page 5 of 11

A NOTE ON THE BLOOD-BRAIN BARRIER
Although not a direct neuronal or neuroprotective effect, PDGF signaling has a significant, perhaps much
more significant, indirect impact on neuronal health due to its effects on pericytes, angiogenesis, and the
blood-brain barrier. As our focus is on the neuroprotective effects of PDGF signaling, we will not review
PDGF’s vascular effects in detail as these have been reviewed elsewhere [24,50,51] . While the role of PDGF
signaling in the blood-brain barrier is not yet fully understood, several lines of evidence demonstrate that
PDGF signaling increases blood-brain barrier permeability, resulting in neuronal damage, while others
have demonstrated positive effects of PDGF signaling on blood-brain barrier function and recovery
after neuronal insults. Examples of the impact, both positive and negative, of PDGF signaling have been
[57]
[59]
[58]
reported for stroke [52-54] , HAND [24,55,56] , Alzheimer’s disease (AD) , Parkinson’s disease (PD) , epilepsy ,
and neuroinflammation [60,61] .
ALZHEIMER’S DISEASE
[62]
AD is a progressive neurodegenerative disease characterized by cognitive decline . One of the hallmarks
[62]
of AD is amyloid-b accumulation which begins decades before clinical diagnosis of the disease . There
is emerging evidence that the PDGF system is involved in AD pathology. For example, PDGF-BB is one
of the cytokines that differs between post-mortem patients with high amyloid-b accumulation loads that
[63]
did not have cognitive symptoms vs. those that did experience cognitive decline . Amyloid-b is produced
[64]
by the proteolytic cleavage of the amyloid precursor protein (APP) and the PDGF system appears to
play a role in APP homeostasis. In astrocytes, PDGF treatment increases sAPPα activity two-fold and this
[65]
effect is blocked by the broad-spectrum tyrosine kinase inhibitor, genistein . Using a recombinant protein
expressing system in Hela cells, Gianni and Zambrano, along with other colleagues, demonstrated that
PDGF-BB can induce γ-secretase mediated APP proteolysis by activating PDGF receptors and found Src
and Rac1 but not ERKs, PI3K or Abl tyrosine kinase were involved in that signaling pathway [66,67] . Further
studies have identified that the cytodomain of APP (containing YENPTY motif) is required for PDGF-
induced APP proteolysis [66,67] .

The mechanism(s) of amyloid-b toxicity in neurons involve both non-specific and receptor-dependent
[69]
pathways [68-70] , including interactions with receptor tyrosine kinases . In SH-SY5Y cells, application of
PDGF-BB increases cell number and this effect is inhibited in the presence of amyloid-b . PDGF-BB-
[71]
induced phosphorylation of the PDGFb receptor is also blocked by amyloid-b, however, no physical
[71]
association between amyloid-b-PDGF-BB was detected . Indirect activation (i.e., transactivation - see
[71]
the section below) was not affected by amyloid-b . We have previously demonstrated that direct or
indirect (GPCR-mediated) activation of the PDGFb receptor can protect neurons against NMDA receptor-
[72]
dependent toxicity . However in the presence of amyloid-b, PDGF-BB application was no longer able to
prevent NMDA-induced toxicity, suggesting that amyloid-b may promote neurodegeneration by blocking a
key neuroprotective pathway in the brain.

PARKINSON’S DISEASE
Similar to AD, there is evidence that PDGF and other neurotrophic factors may also be involved in the
pathogenesis and treatment of PD due to both its neuroprotective and trophic effects (see two recent
reviews [73,74] ). The levels of PDGF-BB and PDGF-AA are correlated with the level of plasma α-synuclein
in PD patients, suggesting PDGF may be a potential biomarker for PD . PDGF-BB provides protective
[75]
effects against a toxicant associated with PD, rotenone, by countering its effects on mitochondria and ROS
production in both cell lines and in astrocytes [76,77] . With the latter finding among those sparking interest
in targeting PDGF signaling in astrocytes in neurologic disease as a therapeutic approach [78,79] . These and
other studies led to human trials with PDGF-BB in phase I clinical trial for PD (a dose-escalation study
[10]
of intracerebroventricular PDGF-BB delivered via an infusion pump, from 0.2 to 5 mg/day) . PDGF-BB