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    The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown. Here, we aimed to investigate astrocyte-related pathological changes of and AβPP using immunohistochemistry and biochemical studies in both animal and cell models. We utilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immuno reactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including up regulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1. Collectively, our results show that age-dependent AβPP up regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD.


    Yingxia Liang, Frank Raven, Joseph F Ward, Sherri Zhen, Siyi Zhang, Haoqi Sun, Sean J Miller, Se Hoon Choi, Rudolph E Tanzi, Can Zhang. Upregulation of Alzheimer's Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo. Journal of Alzheimer's disease : JAD. 2020;76(3):1071-1082

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    PMID: 32597805

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