sAβPPα is a Potent Endogenous Inhibitor of BACE1
Clare Peters-Libeu1, Jesus Campagna2, Michael Mitsumori1
1Buck Institute for Research on Aging, Novato, CA, USA.
Journal of Alzheimer'S Disease : JAD
|September 25, 2015
Summary
Soluble amyloid precursor protein alpha (sAβPPα) directly inhibits the BACE enzyme, a key target in Alzheimer's disease (AD) drug discovery. This finding reveals a new therapeutic strategy for AD and related disorders.
Area of Science:
- Neuroscience
- Biochemistry
- Drug Discovery
Background:
- Amyloid precursor protein (AβPP) cleavage by BACE1 initiates amyloid-β peptide (Aβ) production.
- Aβ overproduction is implicated in Alzheimer's disease (AD), traumatic brain injury, and stroke.
- BACE1 is a primary target for AD drug discovery.
Purpose of the Study:
- To investigate the inhibitory role of sAβPPα on BACE1 activity.
- To elucidate the mechanism of sAβPPα inhibition.
- To explore the structural differences between sAβPPα and sAβPPβ and their impact on BACE1 inhibition.
Main Methods:
- Biochemical assays to assess BACE1 inhibition.
- Small-angle X-ray scattering (SAXS) to determine protein structure.
- Comparative analysis of sAβPPα and sAβPPβ structures and functions.
Main Results:
- sAβPPα is identified as a potent endogenous direct inhibitor of BACE1.
- Inhibition of BACE1 by sAβPPα appears to be allosteric.
- sAβPPβ, lacking 16 amino acids, has a different structure and does not inhibit BACE1.
Conclusions:
- sAβPPα plays a novel role in regulating Aβ production and maintaining neuronal homeostasis.
- sAβPPα acts as a neuroprotective agent by inhibiting BACE1.
- sAβPPα represents a potential therapeutic target for conditions involving Aβ overproduction.
More Related Videos
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
9.2K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
9.2K
01:20The JAK-STAT Signaling Pathway
13.9K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
13.9K
01:24Caspases
14.6K
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
14.6K
01:45Regulation of Nuclear Protein Sorting
3.5K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
3.5K
01:17The Extrinsic Apoptotic Pathway
9.3K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
9.3K
01:58Cell Specific Gene Expression
17.0K
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
17.0K