Clinically, Alzheimer's disease (AD) is characterized by dementia of insidious onset;pathologically, it is characterized by the presence of numerous neuritic plaques, neurofibrillary tangles, and a progressive Neurodegeneration. There is exceedingly strong evidence that abnormal assemblies of A? are neurotoxic and have a key role in AD. Why A? is increased and accumulates or induces Neurodegeneration is unclear. However, the mechanisms of plaque formation and neurodegeneration in AD brains are not clear. We recently described (He et al., 2007) that generation of amyloid 2 (A?), the main component of plaques, is inhibited by TNFRI deletion, which reduces BACE1 levels via the NF-:B pathway. However, we demonstrated in vitro (Shen et al., 1997) that, unlike TNFRI, which is the TNF death receptor, TNFRII, protects neurons. To examine the roles of TNFRII in APP processing, we cross-bred AD transgenic APP23 mice, which express mutant APP and form many A? plaques, with TNFRII knockout mice, to generate TNFRII knockout (TNFRII-/-) in APP23 mice (APP23/TNFRII-/-). Our preliminary results demonstrated that APP23/TNFRII-/- mice have more A? plaques and increased A? levels at 12 months of age. Thus, we propose a central hypothesis that modulation of TNF type II receptor activity can alter BACE1, A? production and AD neuropathology via NF-:B-dependent and independent intracellular signaling pathways. We will use the double transgenic mouse model, APP23/TNFRII-/-, to examine whether these mice exhibit earlier AD-like pathology. If so, we will study the mechanisms, such as possible TNFRII mediated BACE1 through new signal transduction pathways by NF-kB dependent and non-NF-kB dependent manner, and how these mechanisms ultimately result in neuroprotection. We believe that successful completion of the experiments will lead to novel therapeutic interventions. The goal of this application is to determine how TNFRII is regulated in neurons and in mouse brains, how it affects the generation of A? and its precursors, and whether increased production of TNFRII may be protective and ameliorate Neurodegeneration and AD-like disease in mice. We expect to identify modulators of TNFRII expression and proteins that interact with TNFRII. We also expect to establish that TNFRII is a major modifier of AD pathogenesis and that increasing TNFRII levels reduces disease. If successful, our findings may provide new targets for the treatment of AD and neurodegeneration.

Public Health Relevance

Neuronal and synaptic losses are the most prominent features in the Alzheimer's disease (AD) brain. AD treatments are presently inadequate, so numerous novel therapy ideas deserve rigorous exploration in the academic and pharmaceutical research communities. Inhibition of tumor necrosis factor and its mediated signal transduction pathway is one potential target area, like TNF type II receptor (TNFRII) for AD treatment. We recently have started a promising clinical trial with a drug inhibiting TNF signal pathway on AD patients, which is FDA approved and NIH awarded. Thus, elucidating the regulatory mechanisms for BACE1 could identify new potential therapeutic targets and therefore diminish possible side effects that could arise by directly targeting BACE1.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025888-08
Application #
8534659
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Petanceska, Suzana
Project Start
2005-04-01
Project End
2015-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$353,116
Indirect Cost
$126,032
Name
Roskamp Institute, Inc.
Department
Type
DUNS #
119173933
City
Sarasota
State
FL
Country
United States
Zip Code
34243
Tang, Xiaoyu; Wu, Jinglong; Shen, Yong (2016) The interactions of multisensory integration with endogenous and exogenous attention. Neurosci Biobehav Rev 61:208-24
Li, Rena; Cui, Jie; Shen, Yong (2014) Brain sex matters: estrogen in cognition and Alzheimer's disease. Mol Cell Endocrinol 389:13-21
Cheng, Xin; Shen, Yong; Li, Rena (2014) Targeting TNF: a therapeutic strategy for Alzheimer's disease. Drug Discov Today 19:1822-7
Jocham, Gerhard; Klein, Tilmann A; Ullsperger, Markus (2014) Differential modulation of reinforcement learning by D2 dopamine and NMDA glutamate receptor antagonism. J Neurosci 34:13151-62
Sun, Qiying; Hampel, Harald; Blennow, Kaj et al. (2014) Increased plasma TACE activity in subjects with mild cognitive impairment and patients with Alzheimer's disease. J Alzheimers Dis 41:877-86
Cui, Jie; Jothishankar, Balaji; He, Ping et al. (2014) Amyloid precursor protein mutation disrupts reproductive experience-enhanced normal cognitive development in a mouse model of Alzheimer's disease. Mol Neurobiol 49:103-12
Wang, Haibo; Li, Rena; Shen, Yong (2013) β-Secretase: its biology as a therapeutic target in diseases. Trends Pharmacol Sci 34:215-25
Yu, Xiaojun; Du, Tingting; Song, Ning et al. (2013) Decreased iron levels in the temporal cortex in postmortem human brains with Parkinson disease. Neurology 80:492-5
Cui, Jie; Shen, Yong; Li, Rena (2013) Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med 19:197-209
Li, Rena; Shen, Yong (2013) An old method facing a new challenge: re-visiting housekeeping proteins as internal reference control for neuroscience research. Life Sci 92:747-51

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