The Alzheimer disease (AD) brain is characterized by two types of protein aggregates, neurofibrillary tangles (NFTs), comprised of hyperphosphorylated tau, and amyloid plaques, comprised of amyloid-? (A?). Clinically, AD patients show a progressive deterioration of memory and other cognitive functions. Recent evidence points to soluble A? as an excellent candidate for the initial trigger of memory loss;however, the molecular mechanisms underlying A? -induced cognitive decline remain elusive. In our preliminary studies, we have identified the mammalian target of rapamycin (mTOR) as a potential molecular link between A?, tau and cognitive decline. Additionally, we show that A? oligomers increase mTOR signaling, an event mediated by the ?2 adrenergic receptors (?2ARs). To identify the mechanistic link between mTOR signaling and A?, tau and cognitive decline, three Specific Aims are proposed:
Specific Aim 1 will test the hypothesis that the accumulation of A? oligomers increases mTOR activity by a mechanism mediated by ?2ARs. mTOR plays a key role in regulating protein homeostasis;thus, unveiling the molecular pathways leading to its deregulation in AD will lead to a better understanding of the disease pathogenesis. Here we will dissect the molecular pathways that link the A? accumulation to changes in ?2ARs/mTOR signaling.
Specific Aim 2 will test the hypothesis that the A? -induced increase in mTOR signaling further increases A? pathology and exacerbates cognitive decline. Our preliminary data show that mTOR signaling is increased in 3xTg-AD and Tg2576 mice. Additionally, we show that reducing mTOR signaling with rapamycin, a selective mTOR inhibitor, rescues the early neuropathological and behavioral phenotypes in 6-month-old 3xTg-AD mice. Growing evidence shows that rapamycin may have mTOR-independent effects. To directly address the role of mTOR in AD, we will use a genetic approach and knockout mTOR in the brain of the Tg2576 mice.
Specific Aim 3 will test the hypothesis that the increase in mTOR signaling directly contributes to the tau pathology. Our preliminary data show that restoring mTOR signaling in the 3xTg-AD mice suffices to reduce A? and tau pathology. However, the tau pathology in these mice is highly dependent on A? levels;therefore, it remains to be established whether the effects of restoring mTOR signaling on tau pathology are mediated by a direct interaction between mTOR and tau or are simply due to a decrease in A? levels. Using a mouse model overexpressing wild type tau, we will use genetic and pharmacological approaches to decrease mTOR signaling and test the mechanistic link between mTOR signaling and tau pathology. Overall, the proposed Specific Aims will elucidate the underlying molecular pathways linking A?, tau and cognitive decline. The identification of the pathways that lead to cognitive decline may point to new therapeutic targets.

Public Health Relevance

Alzheimer disease is the most common form of dementia among the elderly and the seventh leading cause of death in the United States. Our studies are aimed at understanding the molecular basis underlying memory loss and cognitive in AD decline and will facilitate the identification of potential therapeutic targets for this insidious disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG037637-03
Application #
8505327
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Petanceska, Suzana
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-15
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$306,086
Indirect Cost
$112,361
Name
Banner Health
Department
Type
DUNS #
071753982
City
Phoenix
State
AZ
Country
United States
Zip Code
85006
Caccamo, A; Ferreira, E; Branca, C et al. (2016) p62 improves AD-like pathology by increasing autophagy. Mol Psychiatry :
Ferreira, E; Shaw, D M; Oddo, S (2016) Identification of learning-induced changes in protein networks in the hippocampi of a mouse model of Alzheimer's disease. Transl Psychiatry 6:e849
Velazquez, Ramon; Shaw, Darren M; Caccamo, Antonella et al. (2016) Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease. Mol Neurodegener 11:52
Norambuena, Andrés; Wallrabe, Horst; McMahon, Lloyd et al. (2016) mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease. Alzheimers Dement :
Richardson, Arlan; Galvan, Veronica; Lin, Ai-Ling et al. (2015) How longevity research can lead to therapies for Alzheimer's disease: The rapamycin story. Exp Gerontol 68:51-8
Caccamo, Antonella; Branca, Caterina; Talboom, Joshua S et al. (2015) Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease. J Neurosci 35:14042-56
Mastroeni, Diego; Delvaux, Elaine; Nolz, Jennifer et al. (2015) Aberrant intracellular localization of H3k4me3 demonstrates an early epigenetic phenomenon in Alzheimer's disease. Neurobiol Aging 36:3121-9
Orr, Miranda E; Salinas, Angelica; Buffenstein, Rochelle et al. (2014) Mammalian target of rapamycin hyperactivity mediates the detrimental effects of a high sucrose diet on Alzheimer's disease pathology. Neurobiol Aging 35:1233-42
Branca, Caterina; Wisely, Elena V; Hartman, Lauren K et al. (2014) Administration of a selective β2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease. Neurobiol Aging 35:2726-35
Wisely, Elena V; Xiang, Yang K; Oddo, Salvatore (2014) Genetic suppression of β2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies. Hum Mol Genet 23:4024-34

Showing the most recent 10 out of 16 publications