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Upregulation of Alzheimer's Disease Amyloid-? Protein Precursor in Astrocytes Both in vitro and in vivo.


ABSTRACT:

Background

The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that amyloid-? (A?) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. A? is a proteolytic product of amyloid-? protein precursor (A?PP; 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 A?PP expression in astrocytes and cellular consequences are largely unknown.

Objective

Here, we aimed to investigate astrocyte-related pathological changes of A? and A?PP using immunohistochemistry and biochemical studies in both animal and cell models.

Methods/results

We utilized 5XFAD transgenic mice and found age-dependent upregulation of A?PP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that A?PP proteins presented well-defined punctate immuno reactivity in young animals, whereas A?PP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of A?42 resulted in downstream astrocyte autonomous changes, including up regulation in A?PP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1.

Conclusion

Collectively, our results show that age-dependent A?PP 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.

SUBMITTER: Liang Y 

PROVIDER: S-EPMC7571426 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Upregulation of Alzheimer's Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo.

Liang Yingxia Y   Raven Frank F   Ward Joseph F JF   Zhen Sherri S   Zhang Siyi S   Sun Haoqi H   Miller Sean J SJ   Choi Se Hoon SH   Tanzi Rudolph E RE   Zhang Can C  

Journal of Alzheimer's disease : JAD 20200101 3


<h4>Background</h4>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. Aβ 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  ...[more]

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