Background

Although immune system activation has been observed in patients with Alzheimer's disease (AD), it remains unclear whether inflammatory and/or autoimmune manifestations are epiphenomena, consequence, or cause of brain degeneration. We presently examine whether immunological changes accompany the progress of AD-like disease in well-established 3xTgAD murine model.

Methods

We compared the immunological and behavioral profiles of triple transgenic mice (3xTgAD) and wild type (WT) controls, from 1.5 to 12 months of age. Mice underwent a broad battery of tests to assess longitudinal changes in behavioral performance. FACScan analysis and immunoenzymatic assays were employed to quantify inflammatory and autoimmune markers in serum and spleen.

Results

Prior to the development of advanced AD pathology, 3xTgAD mice developed MCI-like manifestations, characterized by anxiety-related behaviors, changes in olfactory function and impaired flexibility in learning/memory tasks (2.5 months). Several manifestations of systemic inflammatory/autoimmune disease were observed at later age (12 months). They included splenomegaly, elevated serum levels of anti-nuclear and anti-dsDNA antibodies, as well as a reduced number of T splenocytes. Changes in the immune system occurred in parallel with generalized learning/memory and olfaction deficits from 6-12 months of age. However, in 1 year-old 3xTgAD mice, neuropathological changes, as defined by the presence of extracellular plaques and hyperphosphorylated tau, were very mild.

Conclusions

The results suggest that: 1) 3xTgAD mice might develop a systemic autoimmune/inflammatory condition before severe learning/memory deficits emerge. The lack of typical AD brain pathology and profound immune dysfunction suggest that changes in the immune system might be a factor influencing the development of MCI-and subsequent AD-like behavioral dysfunction in the 3xTgAD model 2) 3xTgAD mice display a MCI-like stage of disease development that may be useful in the further study of this phase of cognitive decline.