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.

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 Amyloid-β Oligomers Induce Only Mild Changes to Inhibitory Bouton Dynamics

2021 ◽  
Vol 5 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Marvin Ruiter ◽  
Christine Lützkendorf ◽  
Jian Liang ◽  
Corette J. Wierenga
Keyword(s):  
Hippocampal Slices ◽  
Inhibitory Neuron ◽  
Amyloid Β ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Plaque Load ◽  
Early Alzheimer’S Disease

The amyloid-β protein precursor is highly expressed in a subset of inhibitory neuron in the hippocampus, and inhibitory neurons have been suggested to play an important role in early Alzheimer’s disease plaque load. Here we investigated bouton dynamics in axons of hippocampal interneurons in two independent amyloidosis models. Short-term (24 h) amyloid-β (Aβ)-oligomer application to organotypic hippocampal slices slightly increased inhibitory bouton dynamics, but bouton density and dynamics were unchanged in hippocampus slices of young-adult AppNL - F - G-mice, in which Aβ levels are chronically elevated. These results indicate that loss or defective adaptation of inhibitory synapses are not a major contribution to Aβ-induced hyperexcitability.

scholarly journals Phosphorylation of KLC1 modifies interaction with JIP1 and abolishes the enhanced fast velocity of APP transport by kinesin-1

2017 ◽  
Vol 28 (26) ◽  
pp. 3857-3869 ◽  
Author(s):  
Kyoko Chiba ◽  
Ko-yi Chien ◽  
Yuriko Sobu ◽  
Saori Hata ◽  
Shun Kato ◽  
...  
Keyword(s):  
Coiled Coil ◽  
Amyloid Β ◽  
Tetratricopeptide Repeat ◽  
Amyloid Β Protein ◽  
The Novel ◽  
Anterograde Transport ◽  
Interacting Protein ◽  
Protein Precursor ◽  
Kinesin Light Chain ◽  
Β Protein

In neurons, amyloid β-protein precursor (APP) is transported by binding to kinesin-1, mediated by JNK-interacting protein 1b (JIP1b), which generates the enhanced fast velocity (EFV) and efficient high frequency (EHF) of APP anterograde transport. Previously, we showed that EFV requires conventional interaction between the JIP1b C-terminal region and the kinesin light chain 1 (KLC1) tetratricopeptide repeat, whereas EHF requires a novel interaction between the central region of JIP1b and the coiled-coil domain of KLC1. We found that phosphorylatable Thr466 of KLC1 regulates the conventional interaction with JIP1b. Substitution of Glu for Thr466 abolished this interaction and EFV, but did not impair the novel interaction responsible for EHF. Phosphorylation of KLC1 at Thr466 increased in aged brains, and JIP1 binding to kinesin-1 decreased, suggesting that APP transport is impaired by aging. We conclude that phosphorylation of KLC1 at Thr466 regulates the velocity of transport of APP by kinesin-1 by modulating its interaction with JIP1b.

The upstream stimulatory factor functionally interacts with the Alzheimer amyloid β-protein precursor gene

1995 ◽  
Vol 4 (9) ◽  
pp. 1527-1533 ◽  
Author(s):  
Dora M. Kovacs ◽  
Wilma Wasco ◽  
Johanna Witherby ◽  
Kevin M. Felsenstein ◽  
Franck Brunei ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Upstream Stimulatory Factor ◽  
Protein Precursor ◽  
Β Protein ◽  
Stimulatory Factor

A processing pathway for amyloid β-protein precursor generates a secreted form with an intact carboxyl terminus

Amyloid ◽  
1994 ◽  
Vol 1 (4) ◽  
pp. 221-231 ◽  
Author(s):  
Ramaninder Bhasin ◽  
Luisa Gregori ◽  
Ivan Morozov ◽  
Dmitry Goldgaber
Keyword(s):  
Amyloid Β ◽  
Carboxyl Terminus ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein

Amyloid-β Protein Precursor Deficiency Changes Neuronal Electrical Activity and Levels of Mitochondrial Proteins in the Medial Prefrontal Cortex

2021 ◽  
pp. 1-14
Author(s):  
Qingwei Huo ◽  
Sidra Tabassum ◽  
Ming Chen ◽  
Mengyao Sun ◽  
Yueming Deng ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Amyloid Β ◽  
Neuronal Firing ◽  
Mitochondrial Proteins ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Neuronal Electrical Activity

Background: Neuropathological features of Alzheimer’s disease are characterized by the deposition of amyloid-β (Aβ) plaques and impairments in synaptic activity and memory. However, we know little about the physiological role of amyloid-β protein precursor (AβPP) from which Aβ derives. Objective: Evaluate APP deficiency induced alterations in neuronal electrical activity and mitochondrial protein expression. Methods: Utilizing electrophysiological, biochemical, pharmacological, and behavioral tests, we revealed aberrant local field potential (LFP), extracellular neuronal firing and levels of mitochondrial proteins. Result: We show that APP knockout (APP -/- ) leads to increased gamma oscillations in the medial prefrontal cortex (mPFC) at 1-2 months old, which can be restored by baclofen (Bac), a γ-aminobutyric acid type B receptor (GABABR) agonist. A higher dose and longer exposure time is required for Bac to suppress neuronal firing in APP -/-  mice than in wild type animals, indicating enhanced GABABR mediated activity in the mPFC of APP -/-  mice. In line with increased GABABR function, the glutamine synthetase inhibitor, L-methionine sulfonate, significantly increases GABABR levels in the mPFC of APP -/-  mice and this is associated with a significantly lower incidence of death. The results suggest that APP -/-  mice developed stronger GABABR mediated inhibition. Using HEK 293 as an expression system, we uncover that AβPP functions to suppress GABABR expression. Furthermore, APP -/-  mice show abnormal expression of several mitochondrial proteins. Conclusion: APP deficiency leads to both abnormal network activity involving defected GABABR and mitochondrial dysfunction, suggesting critical role of AβPP in synaptic and network function.

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