Aims

Dysregulation of the Endoplasmic Reticulum (ER) Calcium homeostasis^1-4, and subsequent ER stress activation occur in Alzheimer’s disease (AD). The human truncated isoform of the Sarco-endoplasmic reticulum Calcium ATPase 1 (S1T)⁵ triggers and amplifies ER stress response, leading to subsequent cell commitment to apoptosis through the control of Calcium mobilization from ER to mitochondria⁶. We examined S1T expression in AD and investigated the mutual link between S1T expression and APP processing and neuroinflammation.

Methods

We used SH-SY5Y cells overproducing beta-amyloid precursor protein-derived fragments (APPswe) or treated with oligomeric Amyloid beta (Abeta) peptides, 3xTg-AD transgenic mice and human brains. We used biochemical, quantitative RT-PCR, and sterotaxic injection in 3xTg-AD mice brains.

Results

S1T expression is increased in SH-SY5Y cells expressing APPswe or treated with Abeta oligomers and in sporadic AD brains and is correlated with Abeta load and key ER stress proteins. Overexpression of S1T enhances in return the production of APP C-terminal fragments and Abeta through specific increases of beta-secretase expression and activity. Elevated S1T expression also triggers neuroinflammation in vitro and in vivo⁷.

Conclusions

We describe a molecular interplay between S1T-dependent ER Calcium leak, ER stress and APP processing that could contribute to AD pathogenesis.

1-Oules B,et al. 2012, J Neurosci.

2-Del Prete D, et al. 2014, Mol Neurodegener .

3-Lacampagne A, et al. 2017, Acta Neuropathol.

4-Bussiere R, et al. 2017, J Biol Chem .

5-Chami M, et al. 2001, J Cell Biol.

6-Chami M, et al. 2008, Mol Cell.

7-Bussiere R, et al. 2019, Cells.

Aims

Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) are etiological triggers of Alzheimer’s disease (AD) pathology[1]. Altered mitochondrial homeostasis is also considered as an early event in AD development. Strikingly, we and others demonstrated the localization of APP-derived fragments in mitochondria-associated membranes[2]. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established.

Methods

We used human neuroblastoma SH-SY5Y cells expressing the familial APPswe mutation or C99 fragment. We studied 2xTgAD, 3xTgAD mice and adeno-associated-virus (AAV)-C99 injected mice[3]. To discriminate between APP-CTFs and Abeta, we modulated pharmacologically secretases activity. Finally, we analyzed human post-mortem sporadic AD brains.

Results

We demonstrated in cells, that APP-CTFs fragments induce mitochondrial fragmentation, cristae disorganization, mitochondrial hyperpolarization, and a higher production of mitochondrial ROS, independently of Abeta. Moreover, APP-CTFs trigger mitophagic failure characterized by the activation and accumulation of autophagic markers and mitochondrial proteins. We confirmed the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo. Importantly, we showed that APP-CTFs accumulation correlates with mitophagy failure in AD brains[4].

Conclusions

This study unravels the toxicity of APP-CTFs, independently of Abeta, towards mitochondria dysfunctions and mitophagy in AD. Potential pharmacological approaches should focus on mitophagy activation to force the elimination and/or renewal of harmful mitochondria.

[1] Lauritzen I, et al. Acta Neuropathol 2016.

[2] Del Prete D. et al. J Alzheimers Dis 2017.

[3] Bourgeois A, et al. Neurobiol Aging 2018.

[4] Vaillant-Beuchot L.^#, Mary A.^# (co-authors), Acta Neuropathol 2020, under revision.

Aims

Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) are etiological triggers of Alzheimer’s disease (AD) pathology[1]. Altered mitochondrial homeostasis is also considered as an early event in AD development. Strikingly, we and others demonstrated the localization of APP-derived fragments in mitochondria-associated membranes[2]. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established.

Methods

We used human neuroblastoma SH-SY5Y cells expressing the familial APPswe mutation or C99 fragment. We studied 2xTgAD, 3xTgAD mice and adeno-associated-virus (AAV)-C99 injected mice[3]. To discriminate between APP-CTFs and Abeta, we modulated pharmacologically secretases activity. Finally, we analyzed human post-mortem sporadic AD brains.

Results

We demonstrated in cells, that APP-CTFs fragments induce mitochondrial fragmentation, cristae disorganization, mitochondrial hyperpolarization, and a higher production of mitochondrial ROS, independently of Abeta. Moreover, APP-CTFs trigger mitophagic failure characterized by the activation and accumulation of autophagic markers and mitochondrial proteins. We confirmed the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo. Importantly, we showed that APP-CTFs accumulation correlates with mitophagy failure in AD brains[4].

Conclusions

This study unravels the toxicity of APP-CTFs, independently of Abeta, towards mitochondria dysfunctions and mitophagy in AD. Potential pharmacological approaches should focus on mitophagy activation to force the elimination and/or renewal of harmful mitochondria.

[1] Lauritzen I, et al. Acta Neuropathol 2016.

[2] Del Prete D. et al. J Alzheimers Dis 2017.

[3] Bourgeois A, et al. Neurobiol Aging 2018.

[4] Vaillant-Beuchot L.^#, Mary A.^# (co-authors), Acta Neuropathol 2020, under revision.