Amyloid beta (Abeta), a key pathogenic factor in Alzheimer's disease (AD), accumulates and forms toxic oligomers in the brain as a result of overproduction or inefficient clearance. Thus, pathways regulating Abeta degradation and clearance are prime candidates for therapeutic intervention. We discovered that cathepsin B (CatB), a cysteine protease, degrades Abeta in vitro and in vivo. In more recent studies, we showed that the Abeta -degrading activity of CatB is inhibited by its endogenous inhibitor, cystatin C (CysC), and that reducing CysC enhances CatB- induced Abeta degradation and protects against Abeta -associated synaptic and behavioral deficits. However, unlike some other Abeta degradation enzymes, such as neprilysin (NEP, an endopeptidase with optimal activity at a neutral pH), CatB truncates Abeta at the C-terminus with optimal activity at acidic pHs. CatB also appears to be more effective than NEP in reducing higher orders of Abeta assemblies in vivo. These observations suggest that CatB and NEP may play complementary roles in Abeta degradation. The objectives of this proposal are to determine the cellular mechanisms of the CatB-CysC axis and how it and NEP might work together to regulate Abeta degradation.
In Specific Aim 1, we will assess the effects of the neuronal CatB-CysC axis on Abeta degradation and neuronal synaptic function in vivo. The effects of microglia- and neuron-derived CatB will be compared.
In Specific Aim 2, we will determine if neuronal CatB-CysC axis acts in the endosomal-lysosomal pathway to regulate Abeta degradation. Understanding the subcellular mechanisms of CatB-CysC axis is a prerequisite for the development of therapeutic strategies that target this newly identified pathway.
In Specific Aim 3, we will examine the role of NEP in CatB-induced Abeta degradation and the role of CatB in NEP-induced Abeta degradation. By defining the interplay between the CatB-CysC axis and NEP, new insights into molecular mechanisms regulating Abeta -degradation will likely emerge. Confirmation that the CatB-CysC axis action acts in a complementary manner with NEP would lay the foundation for designing effective Abeta clearance strategies.
This projects aims at investigating mechanisms regulating the catabolism of amyloid beta peptides, a key pathogen in Alzheimer's disease. This study may provide new therapeutic avenue for treating this devastating disease.
|Sohn, Peter Dongmin; Tracy, Tara E; Son, Hye-In et al. (2016) Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment. Mol Neurodegener 11:47|
|Tracy, Tara E; Sohn, Peter Dongmin; Minami, S Sakura et al. (2016) Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss. Neuron 90:245-60|
|Min, Sang-Won; Chen, Xu; Tracy, Tara E et al. (2015) Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21:1154-62|
|Minami, S Sakura; Shen, Vivian; Le, David et al. (2015) Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with Î±7 nicotinic acetylcholine receptor agonists. Biochem Pharmacol 97:454-62|
|Cho, Seo-Hyun; Chen, Jason A; Sayed, Faten et al. (2015) SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1Î². J Neurosci 35:807-18|
|Minami, S Sakura; Min, Sang-Won; Krabbe, Grietje et al. (2014) Progranulin protects against amyloid Î² deposition and toxicity in Alzheimer's disease mouse models. Nat Med 20:1157-64|
|Min, Sang-Won; Sohn, Peter D; Cho, Seo-Hyun et al. (2013) Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Front Aging Neurosci 5:53|
|Grinberg, Lea Tenenholz; Wang, Xuehua; Wang, Chao et al. (2013) Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol 125:581-93|
|Minami, S Sakura; Sun, Binggui; Popat, Ketul et al. (2012) Selective targeting of microglia by quantum dots. J Neuroinflammation 9:22|
|Martens, Lauren Herl; Zhang, Jiasheng; Barmada, Sami J et al. (2012) Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest 122:3955-9|
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