Mechanisms underlying Alzheimer's disease (AD) has progressed based on the 'amyloid cascade hypothesis', which posits that A? deposits primarily contribute to neuronal death and neurofibrillary tangle (NFT) formation. Animal modeling studies support the idea that A? can trigger NFT formation. Therefore, current AD therapy driven by the amyloid hypothesis mostly focuses on reducing cerebral A? levels. However, recent studies showed that A?40 had anti-amyloidogenic effect in vivo thereby suggesting that amyloid therapy targeting A? without any selectivity of single A? species should be approached with caution. We hypothesize that A?40 can attenuate memory impairment and may therefore represent a protective species of A?. To address this hypothesis, we will test the effect of secreted A? on the cognitive function in the rTg4510 mouse model which develops NFTs, neuronal loss and memory impairment in an age-dependent manner. The rTg4510 mice have several advantages such as rapid progression of tau pathology, strong tau expression in a forebrain-specific pattern, and conditional expression of tau. To determine the impact of A?40 in the mouse brain, we will drive A? production using the method of brain-wide transduction of neurons by administering adeno-associated virus (AAV) intracerebroventricularly (i.c.v.) to newborn pups. An AAV construct expressing A?40 or A?42 peptide fused to the C-terminal end of the BRI protein will be utilized so that we can focus our studies specifically on the A?40 or A?42 peptides. This method will allow us to avoid confounding, albeit potentially interesting, effects arising from APP processing derivatives and the subcellular localization of processing. The rTg4510 mice with or without A? peptide expression will be analyzed for cognitive function, brain biochemistry, and neuropathology. If our hypothesis is proven correct, the strategies of selective increases in A?40 levels may be effective at reducing the risk for development of AD. In any case, the results will provide important clues to answer whether A? peptides act to deteriorate cognitive function.

Public Health Relevance

During the last 20 years, our understanding of mechanisms underlying Alzheimer's disease, a progressive neurological disorder with memory loss and confusion, has progressed based on the amyloid hypothesis. Recent study showed that A?40 may have an anti-amyloidogenic effect in vivo suggesting that amyloid therapy targeting A? without any selectivity of specific A? species should be approached with caution. Here, we hypothesize that A?40 may attenuate memory impairment and the strategies of selectively increasing A?40 levels may be effective at reducing the risk for development of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS067127-01
Application #
7769825
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
2009-09-15
Project End
2010-08-31
Budget Start
2009-09-15
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$229,500
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Sahara, Naruhiko; Perez, Pablo D; Lin, Wen-Lang et al. (2014) Age-related decline in white matter integrity in a mouse model of tauopathy: an in vivo diffusion tensor magnetic resonance imaging study. Neurobiol Aging 35:1364-74
Ren, Yan; Lin, Wen-Lang; Sanchez, Laura et al. (2014) Endogenous tau aggregates in oligodendrocytes of rTg4510 mice induced by human P301L tau. J Alzheimers Dis 38:589-600
Ward, Sarah M; Himmelstein, Diana S; Ren, Yan et al. (2014) TOC1: a valuable tool in assessing disease progression in the rTg4510 mouse model of tauopathy. Neurobiol Dis 67:37-48
Perez, Pablo D; Hall, Gabrielle; Kimura, Tetsuya et al. (2013) In vivo functional brain mapping in a conditional mouse model of human tauopathy (tau(P301L)) reveals reduced neural activity in memory formation structures. Mol Neurodegener 8:9
Sahara, Naruhiko; DeTure, Michael; Ren, Yan et al. (2013) Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain. J Alzheimers Dis 33:249-63
de Calignon, Alix; Polydoro, Manuela; Suárez-Calvet, Marc et al. (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685-97
Walker, Lary C; Diamond, Marc I; Duff, Karen E et al. (2012) Mechanisms of Protein Seeding in Neurodegenerative Diseases. Arch Neurol :1-7
Lin, Wen-Lang; Dickson, Dennis W; Sahara, Naruhiko (2011) Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy. J Neuropathol Exp Neurol 70:779-87