Observation of amyloid precursor protein cleavage and Aβ generation in living cells by using multiphoton laser scanning microscopy

Li, Xiaoqing; Zhang, Suming; Yang, Huajing

doi:10.1007/s12264-007-0038-6

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…Very interestingly, recent studies from our group also demonstrated that BR297 efficiently improved neuroblastoma cell bioenergetics by increasing the cellular ATP level and mitochondrial respiration under normal/physiological situations . Consistently, BR297 treatment, which reduced ROS levels, as well as ameliorated mitochondrial respiration and cell survival, was also more effective than AP with respect to preventing oxidative stress‐evoked death of the APP‐transfected neuroblastoma cells that represent a relevant and reliable cell model for the investigation of physio‐pathological mechanisms involved in AD . We have also found that our 3α‐analogue BR351 (O‐allyl‐AP), which strongly promoted the proliferation and protection of neural stem cells against β‐amyloid‐induced death, only slightly stimulated mitochondrial activities .…”

Section: Discussionsupporting

confidence: 68%

“…Because the key neuroendocrine and neuroactive neurosteroid AP exerts pleiotropic actions, including cell proliferation-promoting, neurogenic and neuroprotective effects, its use in the development of targeted therapeutic strategies remains complex. [4][5][6][7][8][9][10][11][12][13][14][15][16]23,35,36,56,57 Therefore, we decided to synthesise AP analogues with the aim of identifying compounds that may have higher efficacy and/or better [65][66][67][68][69][70] We have also found that our 3αanalogue BR351 (O-allyl-AP), which strongly promoted the proliferation and protection of neural stem cells against β-amyloid-induced death, only slightly stimulated mitochondrial activities. 58,71 Therefore, it appears that the subtle structural difference between BR351 and BR297 is sufficient to generate selective activity profiles allowing the possibility of developing a BR351-or BR297-based therapeutic strategy adapted to the pathological conditions that require either neurogenic and neuroprotective effects or only a selective action to protect nerve cells against death without promoting cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

Taleb

Patte‐Mensah

Meyer

et al. 2018

J Neuroendocrinology

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The neurosteroid allopregnanolone (AP) modulates neuroendocrine/neurobiological processes, including hypothalamic-pituitary-adrenocortical activities, pain, anxiety, neurogenesis and neuroprotection. These observations raised the hope of developing AP-based therapies against neuroendocrine and/or neurodegenerative disorders. However, the pleiotropic actions of AP, particularly its cell-proliferation-promoting effects, hamper the development of selective/targeted therapies. For example, although AP-induced neurogenesis may serve to compensate neuronal loss in degenerative brains, AP-evoked cell-proliferation is contraindicated for steroid-sensitive cancer patients. To foster progress, we synthesised 4 novel AP analogues of neurosteroids (ANS) designated BR053 (12-oxo-epi-AP), BR297 (O-allyl-epi-AP), BR351 (O-allyl-AP) and BR338 (12-oxo-AP). First, because AP is well-known as allosteric modulator of GABAA receptors (GABAA-R), we used the electrophysiological patch-clamp technique to determine the structure-activity relationship of our ANS on GABAA-activated current in NCB20 cells expressing functional GABAA-R. We found that the addition of 12-oxo-group did not significantly change the respective positive or negative allosteric effects of 3α-AP or 3β-(epi)-AP analogues. Importantly, substitution of the 3α-hydroxyl-group by 3α-O-allyl highly modified the ANS activities. Unlike AP, BR351 induced a long-lasting desensitisation/inhibition of GABAA-R. Interestingly, replacement of the 3β-hydroxyl by 3β-O-allyl (BR297) completely reversed the activity from negative to positive allosteric action. In a second step, we compared the actions of AP and ANS on SH-SY5Y neuronal cell viability/proliferation using MTT-reduction assays. Different dose-response curves were demonstrated for AP and the ANS. By contrast to AP, BR297 was totally devoid of cell-proliferative effect. Finally, we compared AP and ANS abilities to protect against oxidative stress-induced neuronal death pivotally involved in neurodegenerative diseases. Both BR351 and BR297 had notable advantages over AP in protecting SH-SY5Y cells against oxidative stress-induced death. Thus, BR297 appears to be a potent neuroprotective compound devoid of cell-proliferative activity. Altogether, our results suggest promising perspectives for the development of neurosteroid-based selective and effective strategies against neuroendocrine and/or neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

Taleb

Patte‐Mensah

Meyer

et al. 2018

J Neuroendocrinology

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Allopregnanolone and its analog BR 297 rescue neuronal cells from oxidative stress-induced death through bioenergetic improvement

Lejri¹,

Grimm²,

Miesch³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Allopregnanolone (AP) is supposed to exert beneficial actions including anxiolysis, analgesia, neurogenesis and neuroprotection. However, although mitochondrial dysfunctions are evidenced in neurodegenerative diseases, AP actions against neurodegeneration-induced mitochondrial deficits have never been investigated. Also, the therapeutic exploitation of AP is limited by its difficulty to pass the liver and its rapid clearance after sulfation or glucuronidation of its 3-hydroxyl group. Therefore, the characterization of novel potent neuroprotective analogs of AP may be of great interest. Thus, we synthesized a set of AP analogs (ANS) and investigated their ability to counteract APP-overexpression-evoked bioenergetic deficits and to protect against oxidative stress-induced death of control and APP-transfected SH-SY5Y cells known as a reliable cellular model of Alzheimer's disease (AD). Especially, we examined whether ANS were more efficient than AP to reduce mitochondrial dysfunctions or bioenergetic decrease leading to neuronal cell death. Our results showed that the ANS BR 297 exhibits notable advantages over AP with regards to both protection of mitochondrial functions and reduction of oxidative stress. Indeed, under physiological conditions, BR 297 does not promote cell proliferation but efficiently ameliorates the bioenergetics by increasing cellular ATP level and mitochondrial respiration. Under oxidative stress situations, BR 297 treatment, which decreases ROS levels, improves mitochondrial respiration and cell survival, appears more potent than AP to protect control and APP-transfected cells against HO-induced death. Our findings lend further support to the neuroprotective effects of BR 297 emphasizing this analog as a promising therapeutic tool to counteract age- and AD-related bioenergetic deficits.

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Neural cell cycle dysregulation and central nervous system diseases

Wang

Xie

et al. 2009

Progress in Neurobiology

144

108

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Observation of amyloid precursor protein cleavage and Aβ generation in living cells by using multiphoton laser scanning microscopy

Cited by 3 publications

References 10 publications

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

Allopregnanolone and its analog BR 297 rescue neuronal cells from oxidative stress-induced death through bioenergetic improvement

Neural cell cycle dysregulation and central nervous system diseases

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