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Partial reduction of amyloid ? production by ?-secretase inhibitors does not decrease synaptic transmission.

ABSTRACT: BACKGROUND:Alzheimer's disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of A? peptides, especially A?42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. A? peptides are produced by sequential proteolytic processing of APP, with ?-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inhibitors have been tested in clinical trials, but so far, all have had negative outcomes or even led to worsening of cognitive function. AD can be triggered by A? years before the first symptoms appear and one reason for the failures could be that the clinical trials were initiated too late in the disease process. Another possible explanation could be that BACE inhibition alters physiological APP processing in a manner that impairs synaptic function, causing cognitive deterioration. METHODS:The aim of this study was to investigate if partial BACE inhibition, mimicking the putative protective effect of the Icelandic mutation in the APP gene, could reduce A? generation without affecting synaptic transmission. To investigate this, we used an optical electrophysiology platform, in which effects of compounds on synaptic transmission in cultured neurons can be monitored. We employed this method on primary cortical rat neuronal cultures treated with three different BACE inhibitors (BACE inhibitor IV, LY2886721, and lanabecestat) and monitored A? secretion into the cell media. RESULTS:We found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced A? secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in A? secretion, did not affect synaptic transmission for any of the inhibitors tested. CONCLUSION:Our results indicate that A? production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of A? build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function.

SUBMITTER: Satir TM

PROVIDER: S-EPMC7251689 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission.

Satir Tugce Munise TM Agholme Lotta L Karlsson Anna A Karlsson Mattias M Karila Paul P Illes Sebastian S Bergström Petra P Zetterberg Henrik H

Alzheimer's research & therapy 20200526 1

<h4>Background</h4>Alzheimer's disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of Aβ peptides, especially Aβ42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. Aβ peptides are produced by sequential proteolytic processing of APP, with β-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inh ...[more]

PMID: 32456694

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Project description:BackgroundAmyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied.MethodsTo genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP).ResultsIt is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway.ConclusionsOur findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.

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Partial reduction of amyloid ? production by ?-secretase inhibitors does not decrease synaptic transmission.

Publications

Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission.

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