The aim of our studies is to define the role of the immune system in the development of Alzheimer's Disease (AD). Our clinical studies will determine prospectively if there is a link between a low level of serum anti-Aβ peptide antibodies and cognitive decline in patients with mild cognitive impairment (MCI) or with AD. These studies will test the hypothesis that natural, serum anti-Aβ peptide antibodies protect humans from cerebral Aβ peptide deposits and cognitive decline. We shall use a sensitive and reproducible ELISA to measure serum IgG anti-Aβ peptide antibody titers. In prior studies, this assay revealed that community-residing healthy, elderly, subjects had higher serum anti-Aβ peptide antibody levels than did community-residing patients with mild to moderate AD (Exp. Geront., in press). We will extend these studies to include additional well-characterized patients with mild to moderate AD and compare serum IgG anti-Aβ peptide antibody titers in persons with MCI that have a high versus a low probability of progression to AD. Furthermore, we shall determine whether T cell function in AD patients with low serum, anti-Aβ peptide antibody titers is more impaired than that in AD patients with high serum, anti-Aβ peptide antibody titers.
Our experimental studies will complement and extend the clinical studies. Specifically, we plan to determine the role of the immune system in APP-transgenic mice on the development of cerebral Aβ peptide deposits. C57BL/6 mice lacking both recombinase activating genes (RAG)-1 lack lymphocytes and are therefore immunologically incompetent. We are breeding these mice to heterozygous Tg2576 C57BL/6 mice carrying the APP Sw 670/671 mutation (APP-Tg). When F1 mice are backcrossed to homozygous RAG-1-deficient mice 4 types of littermates will be produced in equal numbers. Fifty percent of the mice will be heterozygous APP-Tg with half being homozygous RAG-1 deficient mice (immune deficient) and half being heterozygous RAG-1 deficient mice (immune competent). The remaining 50% of the mice will lack the APP-Tg with half being homozygous RAG-1 deficient mice (immune deficient) and half being heterozygous RAG-1 deficient mice (immune competent).
If naturally occurring, anti-Aβ peptide antibodies in immune competent mice delay or prevent cerebral Aβ peptide deposits in APP-Tg mice, we expect that immune deficient APP-Tg mice will develop cerebral Aβ peptide deposits more rapidly than their immune competent APP-Tg littermates. Control mice that lack the APP-Tg will be used to determine if RAG-1 gene deficiency affects cerebral Aβ peptide levels and/or deposits in the absence of the APP-Tg.
Because active immunization of APP-Tg mice with Aβ peptides prevents or reverses cerebral Aβ peptide deposition and cognitive impairment, active immunization with Aβ peptides was begun in patients with AD last year. Unfortunately, the phase II studies had to be stopped because of CNS inflammation. The untoward effects of active immunization with Aβ peptides are generally thought to be due to the induction of Aβ peptide-specific cytotoxic T cells. Thus, it is clear that realizing the promise of immunotherapy for AD will require greater knowledge of the mechanisms that link the immune and nervous system. If immune deficient APP-Tg mice develop cerebral Aβ peptide deposits more rapidly than immune competent APP-Tg mice, we shall compare the effect of passive immunization with anti-Aβ peptide antibodies on cerebral Aβ peptide levels and deposits in immunologically competent and incompetent APP-Tg mice. We expect that passive immunization with anti-Aβ peptide antibodies will prevent cerebral Aβ peptide deposition to a comparable extent in immunologically competent or immunologically incompetent APP-Tg mice.