Sequential cleavage of APP by ?- and ?-secretase yields A? peptides that are pathogenic in Alzheimer's Disease (AD), along with AID/AICD, which mediates APP signaling. Some APP and ?-secretase mutations alter the rate of A? production and cause autosomal dominant familial AD (FAD). Given the role of APP processing in AD and APP-mediated functions, modulators of APP cleavage such as BRI2 are biologically relevant and of therapeutic interest. Of note, BRI2 mutations cause autosomal dominant Familial British (FBD) and Familial Danish (FDD) Dementia two AD-like diseases. We have further studied the significance of the BRI2-APP interaction and found that: 1) BRI2 inhibits APP processing and A? generation;2) BRI2 mutants that cause FBD and FDD are poor inhibitors of APP processing. Thus, our WORKING HYPOTHESIS is that: A) BRI2 is a competitive inhibitor of APP cleavage by secretases;B) BRI2 regulates AD pathogenesis;C) FBD and FDD BRI2 mutants exacerbate the progression of AD, and dis- regulation of APP processing may participate in FDD and FBD pathogenesis. This grant has three Aims in which we propose to test these hypotheses.

Public Health Relevance

Alzheimer's disease (AD) is the most common cause of dementia in the world. It is estimated that ~1% of humans aged 60-64 years have AD, increasing steadily to as many as 35%-40% after age 85. AD is caused by the formation of plaques in the brain. These plaques impair the function of neuronal cells and, eventually, cause death of these cells. When the damage is large enough, dementia ensues. These senile plaques are formed by accumulation of a small molecule. Much of the efforts from scientists and industry are concentrated on findings drugs capable of preventing formation of these plaques or promoting the removal of this noxious material. This project proposal aims to study a protein that can diminish the formation of this toxic substance. We hope that our studies will translate into a program to develop drug for altering the course of the disease versus simply treating the symptoms like all of the approved drugs for AD currently are.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033007-04
Application #
8299534
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
2009-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$323,826
Indirect Cost
$128,750
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Del Prete, Dolores; Lombino, Franco; Liu, Xinran et al. (2014) APP is cleaved by Bace1 in pre-synaptic vesicles and establishes a pre-synaptic interactome, via its intracellular domain, with molecular complexes that regulate pre-synaptic vesicles functions. PLoS One 9:e108576
Lombino, Franco; Biundo, Fabrizio; Tamayev, Robert et al. (2013) An intracellular threonine of amyloid-* precursor protein mediates synaptic plasticity deficits and memory loss. PLoS One 8:e57120
Tamayev, Robert; Matsuda, Shuji; Arancio, Ottavio et al. (2012) *- but not ýý-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia. EMBO Mol Med 4:171-9
Tamayev, Robert; D'Adamio, Luciano (2012) Inhibition of ýý-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. Mol Neurodegener 7:19
Tamayev, Robert; D'Adamio, Luciano (2012) Memory deficits of British dementia knock-in mice are prevented by Aýý-precursor protein haploinsufficiency. J Neurosci 32:5481-5
Tamayev, Robert; Matsuda, Shuji; Giliberto, Luca et al. (2011) APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant. EMBO J 30:2501-9
Barbagallo, Alessia P M; Wang, Zilai; Zheng, Hui et al. (2011) A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function. J Biol Chem 286:8717-21
Matsuda, Shuji; Tamayev, Robert; D'Adamio, Luciano (2011) Increased A*PP processing in familial Danish dementia patients. J Alzheimers Dis 27:385-91
Barbagallo, Alessia P M; Wang, Zilai; Zheng, Hui et al. (2011) The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function. PLoS One 6:e18006
Matrone, Carmela; Barbagallo, Alessia P M; La Rosa, Luca R et al. (2011) APP is phosphorylated by TrkA and regulates NGF/TrkA signaling. J Neurosci 31:11756-61

Showing the most recent 10 out of 13 publications