Grant: Operating Grant - Priority Announcement: Aging (Bridge Funding)

Alzheimer disease (AD) is the most common form of dementia. Its pathological hallmarks include profound neuronal loss, presence of intraneuronal neurofibrillary tangles and deposition of beta amyloid protein (A). This disease, although phenotypically manifested as cognitive deficits, exhibits pathologic traits that are suggestive of a systemic disorder. One school of thought puts A at center-stage of immune reactions leading to the development of a chronic inflammatory process. According to this hypothesis, during the early phases of AD, immunity seeks to eliminate the overproduced A in the periphery by mounting a beneficial (acute) inflammatory response, resulting in T cell activation and production of specific antibodies. Thus, the cellular immune response may play a crucial role in protection via antigenic activation. Consistent with such a role in defence, A-reactive cells are also found in healthy persons. However, especially T cell immunity is compromised in the elderly, a state designated: immunosenescence, characterised by the accumulation of dysfunctional end-stage differentiated T cells. These are often associated with infection by the common persistent Herpes virus HHV5 (cytomegalovirus, CMV). However, CMV infection has been linked to cognitive impairment in the elderly in longitudinal studies. CMV might thus be one of the prime driving forces behind many of the alterations associated with immunosenescence and the manner in which CMV and the host immune system interact might also contribute in determining the "age" of adaptive immunity and hence age-associated diseases such as AD. This project is aimed at studying putative relationships between aging, dementia and the impact of CMV in an effort to establish the extent to which disease course may be influenced by the dynamics of the cellular immune response. Such knowledge could lead to novel treatment strategies based on manipulation of immunity and/or viral infection.