Pigment Epithelium-Derived Factor Plays a Role in Alzheimer's Disease by Negatively Regulating Aβ42

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. Pigment epithelium-derived factor (PEDF), a unique neurotrophic protein, decreases with aging. Previous reports have conflicted regarding whether the PEDF concentration is altered in AD patients. In addition, the effect of PEDF on AD has not been documented. Here, we tested serum samples of 31 AD patients and 271 normal controls. We found that compared to PEDF levels in young and middle-aged control subjects, PEDF levels were reduced in old-aged controls and even more so in AD patients. Furthermore, we verified that PEDF expression was much lower and amyloid β-protein (Aβ)42 expression was much higher in senescence-accelerated mouse prone 8 (SAMP8) strain mice than in senescence-accelerated mouse resistant 1 (SAMR1) control strain mice. Accordingly, high levels of Aβ42 were also observed in PEDF knockout (KO) mice. PEDF notably reduced cognitive impairment in the Morris water maze (MWM) and significantly downregulated Aβ42 in SAMP8 mice. Mechanistically, PEDF downregulated presenilin-1 (PS1) expression by inhibiting the c-Jun N-terminal kinase (JNK) pathway. Taken together, our findings demonstrate for the first time that PEDF negatively regulates Aβ42 and that PEDF deficiency with aging might play a crucial role in the development of AD.Electronic supplementary materialThe online version of this article (10.1007/s13311-018-0628-1) contains supplementary material, which is available to authorized users.

PEDF, a pleiotropic WTC-LI biomarker: Machine learning biomarker identification and validation

“…[63] PEDF has been shown to have neurotrophic and neuroprotective effects, and has been implicated in the pathogenesis of Alzheimer's Disease. [64] Additionally MMP-1, a protease which has been implicated in lung fibrosis, interstitial pneumonia, and cancer, was found to be important in our model. [65,66] Proteases have a prominent role in cancer, coronary disease, and OAD.…”

Pigment epithelium‐derived factor (PEDF) and PEDF‐receptor in the adult mouse brain: Differential spatial/temporal localization pattern

“…Therefore, PEDF affects various stem cell populations in the development of bone, brain, muscle, and eye (Sagheer, Gong, & Chung, 2015). PEDF, which promotes survival of retinal ganglion cells through STAT3 activation by PEDFR dependent signaling could be useful in neurodegenerative disorders (Eichler et al, 2017; Huang et al, 2018).…”

“…The most recent publication suggested that PEDF-mediated neuroprotection against oxidant injury is largely mediated via ERK1/2 and Bcl-2, indicating that PEDF preserves the viability of oxidative challenged neurons (Sanchez et al, 2011), and may be related to the inhibition of NADPH oxidase-mediated oxidative stress (Maeda, Matsui, Takeuchi, & Yamagishi, 2011 (Sagheer, Gong, & Chung, 2015). PEDF, which promotes survival of retinal ganglion cells through STAT3 activation by PEDFR dependent signaling could be useful in neurodegenerative disorders (Eichler et al, 2017;Huang et al, 2018).…”

Early Biomarkers of Neurodegenerative and Neurovascular Disorders in Diabetes

“…Regarding neurodegenerative disorders, several studies suggested links between PEDF, EGF, TGF-β and PD/AD [ 113 , 114 , 115 , 116 ]. For example, EGF is lower in plasma of PD patients compared to healthy controls [ 113 ].…”

“…In contrast, elevated level of TGF-β was found in CSF in AD [ 115 ]. Further, in AD the serum level of PEDF was decreased compared to two groups of healthy controls: middle-aged adults and older adults [ 116 ]. Altogether, the role of GFs as biomarkers requires further investigation.…”