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.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia among the elderly, affecting up to 35.6 million people worldwide [1]
Pigment epithelium-derived factor (PEDF) levels were decreased in AD patients and the mouse model, which suggested that PEDF might have an essential role in the AD process
The current study first demonstrated that serum PEDF levels were significantly decreased in AD patients
Summary
Alzheimer’s disease (AD) is the most common cause of dementia among the elderly, affecting up to 35.6 million people worldwide [1]. Senile plaques (SPs) composed of ~ 4-kDa amyloid β-protein (Aβ) fibrils are generally considered as the upstream causative factor as well as a major therapeutic target of AD [2, Mao Huang and Weiwei Qi contributed to this work. Aβ42 comprises less than 10% of secreted Aβ species, Aβ42 is highly prone to aggregation and is the major form of Aβ deposited in SPs [4]. Besides extracellular Aβ42, intracellular Aβ42 aggregation is an early event that may precede extracellular SP formation and contribute to neuronal damage [5,6,7]. The reason for Aβ42 aggregation in AD patients is not well understood
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