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Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Xie C, Ginet V, Sun Y, Koike M, Zhou K, Li T, Li H, Li Q, Wang X, Uchiyama Y, Truttmann AC, Kroemer G, Puyal J, Blomgren K, Zhu C - Autophagy (2016)

Bottom Line: There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI).Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death.Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells.

View Article: PubMed Central - PubMed

Affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.

ABSTRACT
Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

No MeSH data available.


Related in: MedlinePlus

Neuronal Atg7 deficiency reduced hypoxia-ischemia-induced neuronal cell death. (A) Representative Fluoro-Jade (FJ) staining 24 h after HI and the corresponding quantifications of the number of FJ-positive cells (B) in the border zone of the cortical infarction (Cx) (2,093,000 ± 287,600/mm3 vs. 1,259,000 ± 230,200/mm3; *, P<0.05), (C) in the striatum (Str) (1,368,000 ± 46,860/mm3 vs. 912,300 ± 134,100/mm3; **, P < 0.01), (D) in the entire CA1 (209,900 cells ± 14,600 cells/mm3 vs. 167,500 cells ± 12,310 cells/mm3; *, P < 0.05) and (E) in the dentate gyrus (DG) (500,700 cells ± 56,880 cells/mm3 vs. 344,000 cells ± 45,150 cells/mm3; *, P < 0.05, n = 11/group). KO: atg7 KO (Atg7flox/flox; Nes-Cre) and Ctrl: Atg7flox/+; Nes-Cre.
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f0004: Neuronal Atg7 deficiency reduced hypoxia-ischemia-induced neuronal cell death. (A) Representative Fluoro-Jade (FJ) staining 24 h after HI and the corresponding quantifications of the number of FJ-positive cells (B) in the border zone of the cortical infarction (Cx) (2,093,000 ± 287,600/mm3 vs. 1,259,000 ± 230,200/mm3; *, P<0.05), (C) in the striatum (Str) (1,368,000 ± 46,860/mm3 vs. 912,300 ± 134,100/mm3; **, P < 0.01), (D) in the entire CA1 (209,900 cells ± 14,600 cells/mm3 vs. 167,500 cells ± 12,310 cells/mm3; *, P < 0.05) and (E) in the dentate gyrus (DG) (500,700 cells ± 56,880 cells/mm3 vs. 344,000 cells ± 45,150 cells/mm3; *, P < 0.05, n = 11/group). KO: atg7 KO (Atg7flox/flox; Nes-Cre) and Ctrl: Atg7flox/+; Nes-Cre.

Mentions: Neuronal cell death in the cortex and striatum as well as in the dentate gyrus (DG) and the cornu ammonis (CA) was investigated by using Fluoro-Jade staining, a nonspecific neuronal marker of cell death, 24 h after HI (Fig. 4A). The number of Fluoro-Jade-positive neurons in all 4 cerebral regions was significantly reduced in atg7 KO compared to Ctrl mice after HI (Fig. 4B to E).Figure 4.


Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Xie C, Ginet V, Sun Y, Koike M, Zhou K, Li T, Li H, Li Q, Wang X, Uchiyama Y, Truttmann AC, Kroemer G, Puyal J, Blomgren K, Zhu C - Autophagy (2016)

Neuronal Atg7 deficiency reduced hypoxia-ischemia-induced neuronal cell death. (A) Representative Fluoro-Jade (FJ) staining 24 h after HI and the corresponding quantifications of the number of FJ-positive cells (B) in the border zone of the cortical infarction (Cx) (2,093,000 ± 287,600/mm3 vs. 1,259,000 ± 230,200/mm3; *, P<0.05), (C) in the striatum (Str) (1,368,000 ± 46,860/mm3 vs. 912,300 ± 134,100/mm3; **, P < 0.01), (D) in the entire CA1 (209,900 cells ± 14,600 cells/mm3 vs. 167,500 cells ± 12,310 cells/mm3; *, P < 0.05) and (E) in the dentate gyrus (DG) (500,700 cells ± 56,880 cells/mm3 vs. 344,000 cells ± 45,150 cells/mm3; *, P < 0.05, n = 11/group). KO: atg7 KO (Atg7flox/flox; Nes-Cre) and Ctrl: Atg7flox/+; Nes-Cre.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835980&req=5

f0004: Neuronal Atg7 deficiency reduced hypoxia-ischemia-induced neuronal cell death. (A) Representative Fluoro-Jade (FJ) staining 24 h after HI and the corresponding quantifications of the number of FJ-positive cells (B) in the border zone of the cortical infarction (Cx) (2,093,000 ± 287,600/mm3 vs. 1,259,000 ± 230,200/mm3; *, P<0.05), (C) in the striatum (Str) (1,368,000 ± 46,860/mm3 vs. 912,300 ± 134,100/mm3; **, P < 0.01), (D) in the entire CA1 (209,900 cells ± 14,600 cells/mm3 vs. 167,500 cells ± 12,310 cells/mm3; *, P < 0.05) and (E) in the dentate gyrus (DG) (500,700 cells ± 56,880 cells/mm3 vs. 344,000 cells ± 45,150 cells/mm3; *, P < 0.05, n = 11/group). KO: atg7 KO (Atg7flox/flox; Nes-Cre) and Ctrl: Atg7flox/+; Nes-Cre.
Mentions: Neuronal cell death in the cortex and striatum as well as in the dentate gyrus (DG) and the cornu ammonis (CA) was investigated by using Fluoro-Jade staining, a nonspecific neuronal marker of cell death, 24 h after HI (Fig. 4A). The number of Fluoro-Jade-positive neurons in all 4 cerebral regions was significantly reduced in atg7 KO compared to Ctrl mice after HI (Fig. 4B to E).Figure 4.

Bottom Line: There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI).Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death.Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells.

View Article: PubMed Central - PubMed

Affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.

ABSTRACT
Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

No MeSH data available.


Related in: MedlinePlus