Partial reduction of amyloid β production by β-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 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 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 Aβ 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 Aβ 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 Aβ secretion into the cell media. Results: We found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced Aβ secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in Aβ secretion, did not affect synaptic transmission for any of the inhibitors tested. Conclusion: Our results indicate that Aβ 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 Aβ build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function.

Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer’s Disease Dementia

“…Concordantly, recent studies have suggested that the negative effect of BACE inhibitors on cognition might be independent of the presence of brain amyloid and appears reversible after compound washout [41]. Some authors have suggested that lower BACE inhibition may have potential in future trials [39,42,43].…”

Repurposing bromocriptine for Aβ metabolism in Alzheimer’s disease (REBRAnD) study: randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer’s disease with presenilin 1 (PSEN1) mutations

“… 10 A recent report implies that inhibition of less than 50% of Aβ might preserve neuronal signalling because the APP family plays an important role in synaptic plasticity underlying learning and memory. 52 Thus, we designed the clinical trial for PSEN1-AD with the expectation that bromocriptine will become a candidate as a molecularly targeted drug for AD, and especially for PSEN1-AD.…”

Neuroprotective Natural Products for Alzheimer’s Disease

“…One of the major focuses of drug discovery efforts in the AD area has been the development of drug candidates to regulate abnormal Aβ aggregation. Several synthetic drugs have been evaluated in clinical trials, including LY2886721 [ 113 ], AN1792 [ 114 ] and verubecestat [ 115 ], along with monoclonal antibody drugs such as donanemab, which targets Aβ 3–42 [ 116 ] and aducanumab (BIIB037), which targets a conformational epitope found on Aβ [ 117 ]. However, none of them have been successful in the treatment of AD.…”