Abstract
Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.
| Original language | English |
|---|---|
| Pages (from-to) | 307-324 |
| Number of pages | 18 |
| Journal | Journal of Alzheimer's Disease |
| Volume | 54 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Aug 23 2016 |
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Keywords
- Alzheimer's disease
- Bioenergetic metabolism
- Mitochondria
- PARP-1
- PKM2
ASJC Scopus subject areas
- Clinical Psychology
- Geriatrics and Gerontology
- Psychiatry and Mental health
Cite this
Bioenergetic impairment in animal and cellular models of Alzheimer's disease : PARP-1 inhibition rescues metabolic dysfunctions. / Martire, Sara; Fuso, Andrea; Mosca, Luciana; Forte, Elena; Correani, Virginia; Fontana, Mario; Scarpa, Sigfrido; Maras, Bruno; D'Erme, Maria.
In: Journal of Alzheimer's Disease, Vol. 54, No. 1, 23.08.2016, p. 307-324.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Bioenergetic impairment in animal and cellular models of Alzheimer's disease
T2 - PARP-1 inhibition rescues metabolic dysfunctions
AU - Martire, Sara
AU - Fuso, Andrea
AU - Mosca, Luciana
AU - Forte, Elena
AU - Correani, Virginia
AU - Fontana, Mario
AU - Scarpa, Sigfrido
AU - Maras, Bruno
AU - D'Erme, Maria
PY - 2016/8/23
Y1 - 2016/8/23
N2 - Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.
AB - Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.
KW - Alzheimer's disease
KW - Bioenergetic metabolism
KW - Mitochondria
KW - PARP-1
KW - PKM2
UR - http://www.scopus.com/inward/record.url?scp=84984682126&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84984682126&partnerID=8YFLogxK
U2 - 10.3233/JAD-151040
DO - 10.3233/JAD-151040
M3 - Article
AN - SCOPUS:84984682126
VL - 54
SP - 307
EP - 324
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 1
ER -