Abstract
Alzheimer’s disease (AD) is characterized by accumulation of senile amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles causing progressive loss of synapse and neuronal death. Out of the various neuron death modalities, autophagy and apoptosis are reported to be the major death paradigms in AD. However, how these two processes lead to neuronal loss is still inconspicuous. Here we report that under Aβ toxicity, aberrant autophagy is induced with inefficient autophagic flux in neurons. Simultaneous activation of both autophagy and apoptosis are seen in primary cortical neurons as well as in transgenic mice brains. We found that induction of autophagy by rapamycin is detrimental for neurons; whereas downregulation of Beclin1, an important autophagy inducing protein, provides significant protection in Aβ treated neuronal cells by blocking cytochrome-c release from the mitochondria. We further report that downregulation of Puma, a BH3-only pro-apoptotic protein, inhibits the induction of aberrant autophagy and also ameliorates the autophagy flux under the influence of Aβ. Notably, stereotactic administration of shRNAs against Puma and Beclin1 in adult Aβ-infused rat brains inhibits both apoptotic and autophagic pathways. The regulation of both of the death processes is brought about by the direct interaction between Puma and Beclin1 upon Aβ treatment. We conclude that both Beclin1 and Puma play essential roles in the neuronal death caused by the induction of aberrant autophagy in AD and targeting their interaction could be vital to understand the crosstalk of autophagy and apoptosis as well as to develop a potential therapeutic strategy in AD.
Highlights
The underlying pathogenesis of Alzheimer’s disease (AD) is selective synaptic loss followed by the death of neurons leading to memory impairment and dementia
We found a decrease in the cleaved PARP levels in the brains of rats where we downregulated Puma or Beclin1 as compared to that of the Aβ-infused rat brains (Fig. 7A, B, E, F), suggesting that both Puma and Beclin1 play an essential role in the regulation of both autophagy and apoptosis, in determining the fate of neurons in AD
Since we found that downregulation of Puma or Beclin1 leads to a substantial amount of inhibition of autophagy as well as apoptosis, it was imperative to have checked whether these proteins show any kind of interaction between them or not
Summary
The underlying pathogenesis of Alzheimer’s disease (AD) is selective synaptic loss followed by the death of neurons leading to memory impairment and dementia. We treated neuronally differentiated PC12 cells with Aβ for (p53 upregulated modulator of apoptosis) is a potent pro- overnight in the presence of pan-caspase inhibitor (zVAD-FMK) to apoptotic protein like Bim; its role in autophagy is not inhibit apoptosis, rapamycin to induce autophagy, or both zVAD-. Bcl-2 is supposed to have a dual characteristic; it is an FMK (to inhibit apoptosis) and rapamycin (to simultaneously anti-apoptotic protein but can act as an anti-autophagic induce autophagy). There are many levels of induction of autophagy does not play a major role in cell survival regulations and interactions between the autophagic and under Aβ insult, at least in cultured neurons (Fig. 3A–B). Since our previous experiments showed that autophagy induction does not protect neurons from Aβ
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