During the previous project period, a number of new monclonal antibodies were developed and used as probes for the study of the pathogenesis of Alzheimer's Disease. One of these antibodies, Alz- 50, appears to detect the presence of a protein, A68, which is abundant in the brains of patients with Alzheimer's Disease, but is not detectable in the normal adult brain. A68 has been detected in the cerebrospinal fluid of a small number of cases of Alzheimer's Disease. One of these antibodies, Alz-50, appears to detect the presence of a protein, A68, which is abundant in the brains of patients with Alzheimer's Disease, but is not detectable in the normal adult brain. A68 has been detected in the cerebrospinal fluid of a small number of cases of alzheimer's Disease. We have evidence that A68 is present in neurons in the developing human brain, and that it is found in neurons which die during development. In the next project period, we will attempt to test the hypothesis that the presence of A68 in cerebrospinal fluid (CSF) predicts the presence of Alzheimer pathology in the brain. Other monoclonal antibodies detect protein abnormalities in the AD brain: we will assess the potential of these for the prediction of pathologic findings. There is a possibility the patients will produce antibodies to A68: we will attempt to develop techniques for the detection in blood and CSF of such an antibody response. A68 is not present in the majority of plaques found in the brains of non- demented elderly people. We propose to conduct a comprehensive study of possible differences between both plaques and tangles in demented and non-demented elderly subject, employing monoclonal antibodies of A68 and to other proteins. We will continue our studies of the expression of A68-like immunoreactivity in the developing human central nervous system (CNS). In the cerebral cortex, the immunoreactivity is present from about 30 weeks of fetal life until about age 2 years. We have not yet examined other areas of the CNS at each stage of development. We want to extend our developmental studies to the cat brain, where there is excellent data available about the timing of cell birth, migration and cell death. Other animals, such as chick and rat, will be investigated to address specific questions relating to the possible role of A68 in cell death during development. If animal studies suggest a role for A68-like immunoreactivity in cell death, we will develop cell culture systems to examine possible changes in the cell biology of neurons on A68 expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH038623-13
Application #
3486620
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1983-04-01
Project End
1994-03-31
Budget Start
1992-05-01
Budget End
1993-03-31
Support Year
13
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Weinger, Jason G; Davies, Peter; Acker, Christopher M et al. (2012) Mice devoid of Tau have increased susceptibility to neuronal damage in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. J Neuropathol Exp Neurol 71:422-33
Boutajangout, Allal; Ingadottir, Johanna; Davies, Peter et al. (2011) Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem 118:658-67
Davies, Peter; Koppel, Jeremy (2009) Mechanism-based treatments for Alzheimer's disease. Dialogues Clin Neurosci 11:159-69
Herskovits, A Z; Davies, P (2006) The regulation of tau phosphorylation by PCTAIRE 3: implications for the pathogenesis of Alzheimer's disease. Neurobiol Dis 23:398-408
Marambaud, Philippe; Zhao, Haitian; Davies, Peter (2005) Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem 280:37377-82
Andorfer, Cathy; Kress, Yvonne; Espinoza, Marisol et al. (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582-90
Ramakrishnan, Pankajavalli; Dickson, Dennis W; Davies, Peter (2003) Pin1 colocalization with phosphorylated tau in Alzheimer's disease and other tauopathies. Neurobiol Dis 14:251-64
Bu, Bitao; Li, Jin; Davies, Peter et al. (2002) Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model. J Neurosci 22:6515-25
Zamora-Leon, S P; Lee, G; Davies, P et al. (2001) Binding of Fyn to MAP-2c through an SH3 binding domain. Regulation of the interaction by ERK2. J Biol Chem 276:39950-8
Andorfer, C A; Davies, P (2000) PKA phosphorylations on tau: developmental studies in the mouse. Dev Neurosci 22:303-9

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