| Autor: |
Sandberg, Alexandra A., Manning, Evan, Wilkins, Heather M., Mazzarino, Randall, Minckley, Taylor, Swerdlow, Russell H., Patterson, David, Qin, Yan, Linseman, Daniel A. |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
J Alzheimers Dis |
| Popis: |
BACKGROUND: Amyloid beta (Aβ) is a principal cleavage product of amyloid-β precursor protein (AβPP) and is widely recognized as a key pathogenic player in Alzheimer’s disease (AD). Yet, there is increasing evidence of a neurotoxic role for the AβPP intracellular domain (AICD) which has been proposed to occur through its nuclear function. Intriguingly, there is a γ-secretase resident at the mitochondria which could produce AICD locally. OBJECTIVE: We examined the potential of AICD to induce neuronal apoptosis when targeted specifically to the mitochondria and compared its mechanism of neurotoxicity to that of Aβ. METHODS: We utilized transient transfection of HT22 neuronal cells with bicistronic plasmids coding for DsRed and either empty vector (Ires), Aβ, AICD(59), or mitochondrial-targeted AICD (mitoAICD) in combination with various inhibitors of pathways involved in apoptosis. RESULTS: AICD induced significant neuronal apoptosis only when targeted to the mitochondria. Apoptosis required functional mitochondria as neither Aβ nor mitoAICD induced significant toxicity in cells devoid of mitochondrial DNA. Both glutathione and a Bax inhibitor protected HT22 cells from either peptide. However, inhibition of the mitochondrial permeability transition pore only protected from Aβ, while pan-caspase inhibitors uniquely rescued cells from mitoAICD. CONCLUSION: Our results show that AICD displays a novel neurotoxic function when targeted to mitochondria. Moreover, mitoAICD induces apoptosis via a mechanism that is distinct from that of Aβ. These findings suggest that AICD produced locally at mitochondria via organelle-specific γ-secretase could act in a synergistic manner with Aβ to cause mitochondrial dysfunction and neuronal death in AD. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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