Deposition of beta-amyloid peptide (A2) within neuritic plaques is a hallmark pathology of Alzheimer's disease (AD). Processing of the Amyloid Precursor Protein (APP) by 2 and 3-secretases results in the generation of A2 peptides. Excess A2 is believed to be a main contributor to the dysfunction and degeneration of neurons that underlies AD. As such, preventing A2 deposition or clearing excess pathogenic A2 remains an important therapeutic target in AD. APP internalization is required for A2 production and there is evidence that general endocytic dysregulations underlie sporadic AD and AD- like pathophysiologies. Therefore a better understanding of the mechanisms that regulate APP internalization would guide more selective strategies for developing AD therapies. In this proposal we will use biochemical, cell biology and imaging analysis of primary neuronal cultures to test the hypothesis that the novel APP adaptor AIDA-1 regulates A2 production by promoting APP internalization. To determine if AIDA-1 regulates APP metabolism in vivo we will quantify APP proteolytic fragments in newly generated AIDA-1 knockout mice, and determine if loss of AIDA-1 can rescue AD-like phenotypes in mouse models of AD. Moreover we will evaluate the therapeutic potential of cell-permeable peptides that block AIDA-1/APP interactions by determining their effects on excess A2 production in AD mouse models. We will also determine how loss of AIDA-1 affects synaptic function in cell cultures and in acute hippocampal slices from AIDA-1 knockout mice and determine if loss of AIDA-1 can revert the synaptic deficits observed in AD mouse models. With the tools developed here, we will be able to address the chronic and acute effects of loss of AIDA-1 and endogenous A2 production on neurotransmission. This is important given AD has been increasingly viewed as a synaptic dysfunction caused by excess A2 production.
Alzheimer's disease (AD) is the 7th leading cause of death in the United States, with an estimated 5.3 million diseased individuals, resulting in ~172 billion dollars in annual costs (Alzheimer's association 2010 report). Excess beta-amyloid peptides (A2), either soluble or deposited in neuritic plaques are believed to be a main contributor to the dysfunction and degeneration of neurons that occurs in AD. In this proposal we will characterize the role of the novel synaptic component AIDA-1 in the generation of A2 peptides, determine the therapeutic potential of inhibiting AIDA-1 function and determine the effects of AIDA-1 on synaptic transmission.
|Kravchick, Dana O; Karpova, Anna; Hrdinka, Matous et al. (2016) Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity. EMBO J 35:1923-34|
|Klein, Matthew E; Monday, Hannah; Jordan, Bryen A (2016) Proteostasis and RNA Binding Proteins in Synaptic Plasticity and in the Pathogenesis of Neuropsychiatric Disorders. Neural Plast 2016:3857934|
|Younts, Thomas J; Monday, Hannah R; Dudok, Barna et al. (2016) Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release. Neuron 92:479-492|
|Hrdinka, Matous; Sudan, Kritika; Just, Sissy et al. (2016) Normal Development and Function of T Cells in Proline Rich 7 (Prr7) Deficient Mice. PLoS One 11:e0162863|
|Tindi, Jaafar O; Chávez, Andrés E; Cvejic, Svetlana et al. (2015) ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization. J Neurosci 35:8986-96|
|Klein, Matthew E; Castillo, Pablo E; Jordan, Bryen A (2015) Coordination between Translation and Degradation Regulates Inducibility of mGluR-LTD. Cell Rep :|
|Kravchick, Dana O; Jordan, Bryen A (2015) Presynapses go nuclear! EMBO J 34:984-6|
|Klein, Matthew E; Younts, Thomas J; Castillo, Pablo E et al. (2013) RNA-binding protein Sam68 controls synapse number and local ?-actin mRNA metabolism in dendrites. Proc Natl Acad Sci U S A 110:3125-30|
|Mulholland, Patrick J; Jordan, Bryen A; Chandler, L Judson (2012) Chronic ethanol up-regulates the synaptic expression of the nuclear translational regulatory protein AIDA-1 in primary hippocampal neurons. Alcohol 46:569-76|
|Zhang, Guoan; Neubert, Thomas A; Jordan, Bryen A (2012) RNA binding proteins accumulate at the postsynaptic density with synaptic activity. J Neurosci 32:599-609|