Alzheimer's disease (AD) pathology is characterized by neurofibrillary tangles, astrocytosis, microgliosis, and extracellular deposits of ?-amyloid peptides (A?). The A? peptide (40-42 residues) is generated by the constitutive proteolytic processing of the amyloid precursor protein (APP). Many converging lines of evidence suggest that oligomerization and ultimately the deposition of A?42 is an early and critical event in the pathogenesis of AD. In the previous grant period, new strains of mice that express high levels of mutant APP were developed using approaches that utilize tetracycline-regulated vectors. Studies of these mice demonstrated that in an in vivo setting, amyloid deposits are very stable structures that persist long after new production of A? peptides is suppressed. Recently, however, focus has turned away from amyloid deposits as important mediators of cognitive impairment, focusing instead on more soluble oligomeric forms of the peptide. We have devised five Aims to investigate whether amyloid deposits may serve as reservoirs for oligomeric structures that have been implicated as the more potent mediators of cognitive impairment. This question is of major importance in considering therapeutic interventions that target A? production.
Aim 1 will use the tet- regulated transgenic mice to suppress A? production in an environment of high amyloid burden and then use established methods of assessing cognition with passive peripheral transfer of antibodies to A? as a means to determine whether diffusible A? oligomeric inhibitors of memory function persist along with deposited amyloid.
Aim 2 will use a different approach to address whether diffusible species of A? persist along with amyloid deposits;the approach uses transgenic mice expressing mutant APP as recipients of fetal neural grafts from non-transgenic animals. Previous studies have established that the graft environment is very receptive to amyloid deposition. The approach will be to use implant non-transgenic neural grafts in tet-regulated mice with amyloid deposits (and after suppression of new A? production) and then assess whether the grafts take up A? to form new deposits.
Aim 3 proposes to use viral vectors to transduce the grafted cells to express molecules that could be used to further define the nature of these diffusible forms of the peptide.
Aim 4 proposes experiments to ascertain the role of resident microglia in modulating amyloid formation. Using a strain of mice that naturally is deficient in microglia, we will examine the rate, distribution and character of amyloid deposition when crossed to mice that express mutant APP.
Aim 5 proposes to generate new lines of mice that express high levels of mouse A? peptides. Previous studies establish that mouse A? does not promote amyloid deposition;the planned studies will confirm whether this conception is true and examine whether mouse A? (whether in amyloid or not) is capable of influencing cognitive performance. Collectively, these studies address fundamental questions regarding the biology of amyloid deposition and the role of various forms of these A? oligomeric structures in amyloid deposition and cognitive impairment.

Public Health Relevance

Small protein fragments called amyloid beta peptides are crucial mediators of the pathology and symptoms Alzheimer's disease, which is a major cause of disability in the elderly and is currently largely untreatable. Crucial to the disease is the assembly of amyloid peptides into larger structures, which produce molecules that affect systems critical in memory and produce lesions in brain characteristic of the disease called amyloid plaques. The studies proposed in the present application address fundamentally important questions regarding the biology of amyloid peptide assembly into disease-specific structures and the role of such molecules in producing disease-associated symptoms.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Schools of Medicine
United States
Zip Code
Savonenko, Alena V; Melnikova, Tatiana; Wang, Yuchuan et al. (2015) Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation. PLoS One 10:e0129618
Xu, Guilian; Ran, Yong; Fromholt, Susan E et al. (2015) Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits. Acta Neuropathol Commun 3:72
Melnikova, Tatiana; Fromholt, Susan; Kim, HyunSu et al. (2013) Reversible pathologic and cognitive phenotypes in an inducible model of Alzheimer-amyloidosis. J Neurosci 33:3765-79
Njie, eMalick G; Kantorovich, Svetlana; Astary, Garrett W et al. (2012) A preclinical assessment of neural stem cells as delivery vehicles for anti-amyloid therapeutics. PLoS One 7:e34097
Njie, Emalick G; Boelen, Ellen; Stassen, Frank R et al. (2012) Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 33:195.e1-12
Savonenko, Alena V; Melnikova, Tatiana; Hiatt, Andrew et al. (2012) Alzheimer's therapeutics: translation of preclinical science to clinical drug development. Neuropsychopharmacology 37:261-77
Tucker, Stina M Fangmark; Borchelt, David R; Troncoso, Juan C (2008) Limited clearance of pre-existing amyloid plaques after intracerebral injection of Abeta antibodies in two mouse models of Alzheimer disease. J Neuropathol Exp Neurol 67:30-40
Wang, Jiou; Xu, Guilian; Borchelt, David R (2006) Mapping superoxide dismutase 1 domains of non-native interaction: roles of intra- and intermolecular disulfide bonding in aggregation. J Neurochem 96:1277-88
Jankowsky, Joanna L; Slunt, Hilda H; Gonzales, Victoria et al. (2005) Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med 2:e355
Wang, Jiou; Xu, Guilian; Li, Hong et al. (2005) Somatodendritic accumulation of misfolded SOD1-L126Z in motor neurons mediates degeneration: alphaB-crystallin modulates aggregation. Hum Mol Genet 14:2335-47