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

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.

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

Molecular Biology of the Cell ◽

10.1091/mbc.e17-05-0303 ◽

2017 ◽

Vol 28 (26) ◽

pp. 3857-3869 ◽

Cited By ~ 4

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.

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

Human Molecular Genetics ◽

10.1093/hmg/4.9.1527 ◽

1995 ◽

Vol 4 (9) ◽

pp. 1527-1533 ◽

Cited By ~ 30

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

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The amyloid β protein precursor or proteinase nexin II from mouse is closer related to its human homolog than previously reported

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression ◽

10.1016/0167-4781(91)90231-a ◽

1991 ◽

Vol 1129 (1) ◽

pp. 141-143 ◽

Cited By ~ 23

Author(s):

B. De Strooper ◽

F. Van Leuven ◽

H. Van Den Berghe

Keyword(s):

Amyloid Β ◽

Amyloid Β Protein ◽

Human Homolog ◽

Protein Precursor ◽

Β Protein

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

Journal of Alzheimer s Disease ◽

10.3233/jad-201557 ◽

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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