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From the Gladstone Institute of Neurological
Disease*
and the Departments of
Neurology
and
Pathology,¶
University of California, San
Francisco, California; Elan Pharmaceuticals,
South San Francisco, California; and the Departments of Molecular
Biology and Medicine,§
Research Center for
Advanced Science and Technology, University of Tokyo, Tokyo, Japan
The class A scavenger receptor (SR) is expressed on reactive microglia surrounding cerebral amyloid plaques in Alzheimer’s disease (AD). Interactions between the SR and amyloid ß peptides (Aß) in microglial cultures elicit phagocytosis of Aß aggregates and release of neurotoxins. To assess the role of the SR in amyloid clearance and Aß-associated neurodegeneration in vivo, we used the platelet-derived growth factor promoter to express human amyloid protein precursors (hAPPs) in neurons of transgenic mice. With increasing age, hAPP mice develop AD-like amyloid plaques. We bred heterozygous hAPP (hAPP+/-) mice that were wild type for SR (SR+/+) with SR knockout (SR-/-) mice. Crosses among the resulting hAPP+/-SR+/- offspring yielded hAPP+/- and hAPP-/- littermates that were SR+/+ or SR-/-. These second-generation mice were analyzed at 6 and 12 months of age for extent of cerebral amyloid deposition and loss of synaptophysin-immunoreactive presynaptic terminals. hAPP-/-SR-/- mice showed no lack of SR expression, plaque formation, or synaptic degeneration, indicating that lack of SR expression does not result in significant accumulation of endogenous amyloidogenic or neurotoxic factors. In hAPP+/- mice, ablation of SR expression did not alter number, extent, distribution, or age-dependent accumulation of plaques; nor did it affect synaptic degeneration. Our results do not support a critical pathogenic role for microglial SR expression in neurodegenerative alterations associated with cerebral ß amyloidosis.
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