Transsynaptic degeneration of corticocortical pathways is a central mechanism for the propagation of pathology an cell death in systems degenertions involving the cerebral cortex, including Alzheimer's disease. We propose that this type of degeneration may represent an appropriate and realistic target of pathogenic events in these disorders. In the present proposal, we focus on a very reliable in vivo model of transsynaptic cortical degeneration that we have recently developed, i.e., the apoptotic death of pyramidal neurons in the piriform cortex after their disconnection from the olfactory bulb. We investigate specific cellular/molecular events subsequent to bulbotomy such as excitotoxic-type alterations of distal dendrites of deafferented neurons, NOS/No signaling impacting on these neurons; and cell cycle and death genes such as Cyclin D1 and bax. To confirm data from anatomical/expression experiments, we use a number of pharmacological interventions, including: protein synthesis inhibitors that influence apoptosis but not excitotoxicity; small molecules that target glutamate synthesis, release and binding to block excitotoxicity and, in so doing, ameliorate of abolish apoptotic cortical cell death; NOS inhibitors/NO scavengers; cyclin-dependent kinase inhibitors to block cyclin signaling; and caspase inhibitors. We also use mice with genetic advantages that prevent apoptotic neuronal death (e.g., nNOS nulls, bax nulls, ICE-dominant negative Tgs). We expect that these carefully controlled investigations will shed light on critical intermediate mechanisms of cortical degenerations and will suggest clinically advantageous methods to treat these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016263-05
Application #
6726168
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Wise, Bradley C
Project Start
2000-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2006-03-31
Support Year
5
Fiscal Year
2004
Total Cost
$387,977
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rossi, Sharyn L; Mahairaki, Vasiliki; Zhou, Lijun et al. (2014) Remodeling of the piriform cortex after lesion in adult rodents. Neuroreport 25:1006-12
Mahairaki, Vasiliki; Xu, Leyan; Farah, Mohamed H et al. (2009) Targeted knock-down of neuronal nitric oxide synthase expression in basal forebrain with RNA interference. J Neurosci Methods 179:292-9
Zhou, Lijun; Welsh, Annie M; Chen, David et al. (2007) NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: evidence for a nitric oxide-mediated effect involving inhibitory interneurons. Neuropharmacology 52:1528-37
Koliatsos, Vassilis E; Kecojevic, Aleksandar; Troncoso, Juan C et al. (2006) Early involvement of small inhibitory cortical interneurons in Alzheimer's disease. Acta Neuropathol 112:147-62
Bora, Susan H; Liu, Zhiping; Kecojevic, Aleksandar et al. (2005) Direct, complex effects of estrogens on basal forebrain cholinergic neurons. Exp Neurol 194:506-22
Koliatsos, V E; Dawson, T M; Kecojevic, A et al. (2004) Cortical interneurons become activated by deafferentation and instruct the apoptosis of pyramidal neurons. Proc Natl Acad Sci U S A 101:14264-9
Liu, Z; Gastard, M; Verina, T et al. (2001) Estrogens modulate experimentally induced apoptosis of granule cells in the adult hippocampus. J Comp Neurol 441:1-8