Inflammation dependent cerebral deposition of serum amyloid A proteins in amyloid mouse model

The major pathological hallmark of amyloid diseases is the presence of extracellular amyloid deposits. Alzheimer's disease, the most common form of amyloidosis, results from the deposition of amyloid β peptide in the brain. The development of transgenic mice that express mutated forms of the amyloid precursor protein have been beneficial in helping to understand the process of amyloidosis. However, key questions concerning the pathogenesis of Alzheimer's disease are still unanswered: what are the effects of age on amyloid deposition? What role does inflammation play in the process? Here, a novel mouse model of amyloidosis was generated, which expresses the amyloidogenic mouse Saa1 protein in the brain, to address these questions. Serum amyloid A is an apolipoprotein, primarily produced in the liver, and serum protein levels can increase 1000-fold following inflammation. Serum amyloid A is the precursor to the amyloid A protein found in systemic amyloid A amyloid (AA or reactive amyloidosis) deposits in both mouse and man. Using the rat synapsin I promoter, brains of transgenic mice express both RNA and protein for the Saa1 gene. Under non-inflammatory conditions, transgenic mice did not show deposition of amyloid A amyloid in the brain even in mice of advanced age, however, induction of a systemic acute-phase response in transgenic mice promoted amyloid deposition. Amyloid A amyloid deposits were associated with activated astrocytes. Results also showed that aged transgenic mice are more sensitive to inflammation induced amyloid deposition. In addition, the presence of cerebral amyloid angiopathy in the brains of transgenic mice suggests a role for neuronal derived vascular amyloid deposition. Induction of a systemic acute phase response also induced early amyloid β deposition in mutant human amyloid precursor protein transgenic mice. Injection of indomethacin (non-steroidal anti-inflammatory drug) reduced inflammation and amyloid deposition in the Saa1 transgenic mice. These studies indicate that inflammation plays a causative role in amyloid formation and anti-inflammatory drugs can be used to reduce the progression of Alzheimer's disease or prevent it.