Is there a form of benign brain amyloidosis in aging? Although relatively rare, the identification of aged individuals with significant amyloid pathology (lacking tauopathy) that are cognitively normal is one of the lines of evidence that argues against the notion that amyloid-? (A?) deposition is a direct mediator of cognitive decline. Our study seeks a potential explanation for cases of amyloidosis that appear benign by testing the hypothesis that the brains of these pathologic aging (PA) individuals, as compared to Alzheimer disease (AD) brain, contain a distinct conformer of A? assembly that is essentially benign. One potential explanation for amyloid pathology that is benign, in regard to cognition, is that A? may assemble into structures that are conformationally distinct, with some conformations possessing an activity that diminishes cognitive function while others do not. To address this question, we will take advantage of recent studies that have shown that rate and character of amyloid deposition in vulnerable transgenic mice can be greatly influenced by injecting homogenates from human Alzheimer?s disease (AD) brains into their brains. Our preliminary studies, presented below, demonstrate that we have extended this model system to include brain homogenates of PA brains. As expected, we observed robust acceleration of A? pathology in transgenic APPswe/ind mice that were injected with two different AD brain homogenates. Although less consistent, we similarly observed accelerated amyloid pathology in mice injected with brain homogenates from 4 PA cases, with one seeding comparably to AD brain. We propose to seed the brains of two distinct lines of transgenic mice that develop amyloid pathology late in life with homogenates from AD and PA brains, and then assess whether pathology induced in these animals causes cognitive impairment. If PA represents a form of A? amyloidosis that is benign, then we would expect that only the mice seeded with AD homogenates will develop cognitive deficits. Apart from clarifying the distinction between PA and AD, our study may have therapeutic implications. If there are forms of A? amyloidosis that are benign, then it might be possible to chemically modulate the conformer of A? that is associated with cognitive decline to favor the benign forms and thus reduce the burden of A? assemblies that diminish cognitive function.
Our study seeks a potential explanation for cases of Alzheimer-amyloidosis that appear benign by testing the hypothesis that the brains of these pathologic aging (PA) individuals, as compared to Alzheimer disease (AD) brain, contain a distinct conformer of A? assembly that is essentially benign. To address this question, we will take advantage of recent studies that have shown that rate and character of amyloid deposition in vulnerable transgenic mice can be greatly influenced by injecting homogenates from human brain into these mouse brains, a technique termed seeding. We propose to seed the brains of two distinct lines of transgenic mice that develop amyloid pathology late in life with homogenates from AD and PA brains, and then assess whether pathology induced in these animals causes cognitive impairment.
