Anti-Stroke Chinese Herbal Medicines Inhibit Abnormal Amyloid-β Protein Precursor Processing in Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Yan Tan ◽  
Jiani Zhang ◽  
Ke Yang ◽  
Zihui Xu ◽  
Huawei Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Herbal Medicines ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Chinese Herbal Medicines ◽  
Protein Precursor ◽  
Chinese Herbal ◽  
Β Protein ◽  
Aβ Production ◽  
Bace1 Activity

Background: Chinese Herbal Medicines (CHMs), as an important and integral part of a larger system of medicine practiced in China, called Traditional Chinese Medicine (TCM), have been used in stroke therapy for centuries. A large body of studies suggest that some Chinese herbs can help reverse cognitive impairment in stroke patients, while whether these herbs also exert therapeutic benefits for Alzheimer’s disease remains to be seen. Objective: To address this issue, we selected four types of CHMs that are commonly prescribed for stroke treatment in clinical practice, namely DengZhanXiXin (D1), TongLuoJiuNao (T2), QingKaiLing (Q3), and HuangQinGan (H4), and tested their effects on amyloid-β protein precursor (AβPP) processing in vitro. Methods: AβPP, β-secretase (BACE1), and 99-amino acid C-terminal fragment of AβPP (C99) stably transfected cells were used for the tests of AβPP processing. The production of Aβ, activity of BACE1, neprilysin (NEP), and γ-secretase were assessed by ELISA, RT-PCR, and western blot. Results: By upregulating BACE1 activity, D1 increased Aβ production whereas decreased the ratio of Aβ 42/Aβ 40; by downregulating BACE1 activity and modulating the expression of γ-secretase, T2 decreased Aβ production and the ratio of Aβ 42/Aβ 40; by downregulating BACE1 activity, Q3 decreased Aβ production; H4 did not change Aβ production due to the simultaneously downregulation of BACE1 and NEP activity. Conclusion: Our study indicates that these four anti-stroke CHMs regulate AβPP processing through different mechanisms. Particularly, T2 with relatively simple components and prominent effect on AβPP processing may be a promising candidate for the treatment of AD.

scholarly journals The Tottori (D7N) and English (H6R) Familial Alzheimer Disease Mutations Accelerate Aβ Fibril Formation without Increasing Protofibril Formation

2006 ◽  
Vol 282 (7) ◽  
pp. 4916-4923 ◽  
Author(s):  
Yukiko Hori ◽  
Tadafumi Hashimoto ◽  
Yosuke Wakutani ◽  
Katsuya Urakami ◽  
Kenji Nakashima ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Amyloid Fibril Formation ◽  
Β Protein ◽  
Familial Alzheimer Disease ◽  
Aβ Production

A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid β-protein precursor or presenilins. Whereas some amyloid β-protein precursor mutations alter its metabolism through effects on Aβ production, the pathogenic effects of those that alter amino acid residues within the Aβ sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-Aβ mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect Aβ production, synthetic Aβ(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using Aβ(1-40)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R Aβ were markedly inhibited despite enhanced fibril formation. These N-terminal Aβ mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of Aβ peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.

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