BAD-mediated Neuronal Apoptosis and Neuroinflammation Contribute to Alzheimer's Disease Pathology

Overview

Journal iScience

Publisher Cell Press

Date 2021 Aug 25

PMID 34430820

Citations 20

Authors

Liansheng Zhang

Yun Qian

Jie Li

Xuan Zhou

He Xu

Jie Yan

Jialing Xiang

Xiang Yuan

Beicheng Sun

Sangram S Sisodia

Yong-Hui Jiang

Xiaohua Cao

Naihe Jing

Anning Lin

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. However, the underlying molecular mechanism is incompletely understood. Here we report that the pro-apoptotic protein BAD as a key regulator for neuronal apoptosis, neuroinflammation and Aβ clearance in AD. BAD pro-apoptotic activity is significantly increased in neurons of AD patients and 5XFAD mice. Conversely, genetic disruption of alleles restores spatial learning and memory deficits in 5XFAD mice. Mechanistically, phosphorylation and inactivation of BAD by neurotropic factor-activated Akt is abrogated in neurons under AD condition. Through reactive oxygen species (ROS)-oxidized mitochondrial DNA (mtDNA) axis, BAD also promotes microglial NLRP3 inflammasome activation, thereby skewing microglia toward neuroinflammatory microglia to inhibit microglial phagocytosis of Aβ in AD mice. Our results support a model in which BAD contributes to AD pathologies by driving neuronal apoptosis and neuroinflammation but suppressing microglial phagocytosis of Aβ, suggesting that BAD is a potential therapeutic target for AD.

Citing Articles

Comprehension of gut microbiota and microRNAs may contribute to the development of innovative treatment tactics against metabolic disorders and psychiatric disorders.

Nakashima M, Suga N, Fukumoto A, Yoshikawa S, Matsuda S Int J Physiol Pathophysiol Pharmacol. 2025; 16(6):111-125.

PMID: 39850247 PMC: 11751546. DOI: 10.62347/WAZH2090.

Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.

Uremis N, Uremis M J Biochem Mol Toxicol. 2025; 39(1):e70133.

PMID: 39799559 PMC: 11725306. DOI: 10.1002/jbt.70133.

The Interplay Between Accumulation of Amyloid-Beta and Tau Proteins, PANoptosis, and Inflammation in Alzheimer's Disease.

Zhuang X, Lin J, Song Y, Ban R, Zhao X, Xia Z Neuromolecular Med. 2025; 27(1):2.

PMID: 39751702 DOI: 10.1007/s12017-024-08815-z.

The Protective Role of Baicalin in the Regulation of NLRP3 Inflammasome in Different Diseases.

Zhang Q, Guo S, Wang H Cell Biochem Biophys. 2024; .

PMID: 39443419 DOI: 10.1007/s12013-024-01597-y.

The complex effects of miR-146a in the pathogenesis of Alzheimer's disease.

Long Y, Liu J, Wang Y, Guo H, Cui G Neural Regen Res. 2024; 20(5):1309-1323.

PMID: 39075895 PMC: 11624861. DOI: 10.4103/NRR.NRR-D-23-01566.

References

Su J, Kesslak J, Head E, Cotman C . Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer's disease and Down's syndrome brain. Acta Neuropathol. 2002; 104(1):1-6. DOI: 10.1007/s00401-002-0548-2. View

Venegas C, Kumar S, Franklin B, Dierkes T, Brinkschulte R, Tejera D . Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2018; 552(7685):355-361. DOI: 10.1038/nature25158. View

Feng J, Meng C, Xing D . Aβ induces PUMA activation: a new mechanism for Aβ-mediated neuronal apoptosis. Neurobiol Aging. 2014; 36(2):789-800. DOI: 10.1016/j.neurobiolaging.2014.10.007. View

Yi J, Baek S, Heo S, Park H, Kwon H, Lee S . Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity. Neuropharmacology. 2017; 128:282-292. DOI: 10.1016/j.neuropharm.2017.10.028. View

Yan J, Xiang J, Lin Y, Ma J, Zhang J, Zhang H . Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation. Cell. 2013; 152(1-2):304-15. PMC: 3586589. DOI: 10.1016/j.cell.2012.12.021. View

Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M . Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 2005; 120(5):649-61. DOI: 10.1016/j.cell.2004.12.041. View

Kudo W, Lee H, Smith M, Zhu X, Matsuyama S, Lee H . Inhibition of Bax protects neuronal cells from oligomeric Aβ neurotoxicity. Cell Death Dis. 2012; 3:e309. PMC: 3366077. DOI: 10.1038/cddis.2012.43. View

Ohno M, Sametsky E, Younkin L, Oakley H, Younkin S, Citron M . BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron. 2004; 41(1):27-33. DOI: 10.1016/s0896-6273(03)00810-9. View

Heneka M, Golenbock D, Latz E . Innate immunity in Alzheimer's disease. Nat Immunol. 2015; 16(3):229-36. DOI: 10.1038/ni.3102. View

10.

Peng S, Wuu J, Mufson E, Fahnestock M . Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem. 2005; 93(6):1412-21. DOI: 10.1111/j.1471-4159.2005.03135.x. View

11.

Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin X . New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018; 560(7717):198-203. PMC: 6329306. DOI: 10.1038/s41586-018-0372-z. View

12.

Rohn T, Vyas V, Hernandez-Estrada T, Nichol K, Christie L, Head E . Lack of pathology in a triple transgenic mouse model of Alzheimer's disease after overexpression of the anti-apoptotic protein Bcl-2. J Neurosci. 2008; 28(12):3051-9. PMC: 6670712. DOI: 10.1523/JNEUROSCI.5620-07.2008. View

13.

Yue W, Li Y, Zhang T, Jiang M, Qian Y, Zhang M . ESC-Derived Basal Forebrain Cholinergic Neurons Ameliorate the Cognitive Symptoms Associated with Alzheimer's Disease in Mouse Models. Stem Cell Reports. 2015; 5(5):776-790. PMC: 4649256. DOI: 10.1016/j.stemcr.2015.09.010. View

14.

Ghosal K, Vogt D, Liang M, Shen Y, Lamb B, Pimplikar S . Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A. 2009; 106(43):18367-72. PMC: 2762847. DOI: 10.1073/pnas.0907652106. View

15.

Wang H, Pathan N, Ethell I, Krajewski S, Yamaguchi Y, Shibasaki F . Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science. 1999; 284(5412):339-43. DOI: 10.1126/science.284.5412.339. View

16.

Shi Q, Chowdhury S, Ma R, Le K, Hong S, Caldarone B . Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017; 9(392). PMC: 6936623. DOI: 10.1126/scitranslmed.aaf6295. View

17.

Nagahara A, Merrill D, Coppola G, Tsukada S, Schroeder B, Shaked G . Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 2009; 15(3):331-7. PMC: 2838375. DOI: 10.1038/nm.1912. View

18.

Caccamo A, Branca C, Piras I, Ferreira E, Huentelman M, Liang W . Necroptosis activation in Alzheimer's disease. Nat Neurosci. 2017; 20(9):1236-1246. DOI: 10.1038/nn.4608. View

19.

Nicoll R . A Brief History of Long-Term Potentiation. Neuron. 2017; 93(2):281-290. DOI: 10.1016/j.neuron.2016.12.015. View

20.

Finkbeiner S . CREB couples neurotrophin signals to survival messages. Neuron. 2000; 25(1):11-4. DOI: 10.1016/s0896-6273(00)80866-1. View