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Amyloid in Alzheimer’s Disease and Animal Models

  • D. L. Price
  • B. T. Lamb
  • J. D. Gearhart
  • L. J. Martin
  • L. C. Walker
  • E. H. Koo
  • D. R. Borchelt
  • S. S. Sisodia
Part of the Research and Perspectives in Alzheimer’s Disease book series (ALZHEIMER)

Summary

Animal models provide unique opportunities to analyze mechanisms of βamyloid protein (Aβ) amyloidogenesis. One set of studies in control animals was designed to identify the neural cells that express the amyloid precursor protein (APP) and to characterize the transport and processing of APP in vivo. APP is synthesized by neurons and transported by fast axonal transport to terminals, where it may play a role in cell-cell and synaptic interactions. A second group of investigations focused on amyloidogenesis in aged nonhuman primates. In late middle life, monkeys develop age-associated impairments in performance on cognitive/memory tasks and begin to show brain abnormalities, including deposits of Aβ and formation of neurites. Amyloid is readily demonstrable in proximity to APP-enriched swollen axonal terminals and dendrites, suggesting that neurons may be one source of Aβ. However, in ways not yet clear, astrocytes, microglia, and vascular cells may also contribute to the formation of Aβ. In the neuropil of brain, alterations in the normal biology of APP may lead not only to the formation of amyloid fibrils but may also impair synaptic interactions, resulting in synaptic disjunction and disconnection. More recently, in a third set of experiments, we have begun to examine transgenic mice, generated by the yeast artificial chromosome (YAC)-embryonic stem (ES) cell technique. These animals express the entire human APP gene and transgene expression that approximates levels of endogenous APP. These mice, trisomic for APP, may develop Alzheimer’s disease (AD)-type pathology, as occurs in individuals with Down’s syndrome (trisomy 21). Finally, recent research is designed to produce transgenic mice with AD-linked APP mutations; these studies are essential for determining some of the genetic/molecular/biochemical mechanisms that cause AD-type brain lesions in familial AD (FAD). The strategies that have proved valuable in aged monkeys will be very helpful in studies of these mice. Both nonhuman primate and transgenic models will permit the testing of therapeutic approaches designed to ameliorate some of the abnormalities that occur in humans with AD. In conclusion, this review summarizes briefly the features of AD relevant to these studies and outlines some of our research focusing on the biology of APP in neural tissues and animal models, including aged nonhuman primates and transgenic mice.

Keywords

Dorsal Root Ganglion Amyloid Precursor Protein Senile Plaque Yeast Artificial Chromosome Neurobiol Aging 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • D. L. Price
    • 1
  • B. T. Lamb
  • J. D. Gearhart
  • L. J. Martin
  • L. C. Walker
  • E. H. Koo
  • D. R. Borchelt
  • S. S. Sisodia
  1. 1.Neuropathology LaboratoryThe Johns Hopkins University School of MedicineBaltimoreUSA

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