During the next two decades, 78 million individuals are expected to turn 65 years of age in our country alone (the "baby boomer" generation), and the number of individuals over the age of 85 will increase 5-fold. Therefore, the number of individuals with Alzheimer's disease will also increase exponentially. Individuals with Down's syndrome (PS) develop the neuropathological hallmarks of AD early in life, and most also experience dementia with age. In the previous grant period, we characterized a novel animal model for AD. mice with a segmental trisomy of chromosome 16 (Ts65Dn mice). The distal segment of mouse chromosome 16 is homologous to nearly the entire long arm of human chromosome 21, including the gene for amyloid precursor protein (APP), making this an interesting and useful model for AD. We found that these mice undergo a significant deterioration in working and reference memory as young adults (6 months of age), paralleled with an age-dependent elevation in APP and amyloid levels, reduction in growth factor levels and progressive loss of cholinergic neurons in the basal forebrain. There are still a number of key questions that need to be answered in terms of the degenerative process, both in this animal model and in the AD and DS brains: 1)What is the hierarchy of the degenerative process in the Ts65Dn (and the AD) brain?, 2) Is there a mobilization of defense mechanisms in the brain, and if so, when are they mobilized and when are they saturated?, and, finally, 3) Do the cholinergic cells actually die, or do they undergo "phenotypic silencing"? These are key questions that can be translated also to the AD and DS brain. The overall hypothesis of this proposal is:" Growth factor and amyloid systems interact in the AD brain, leading to deteriorating cholinergic function by means of oxidative stress and/or activation of inflammatory pathways". We propose to investigate this hypothesis by four different aims, which include investigations of the young and aged Ts65Dn mouse during normal conditions and when exposed to antioxidant and anti- inflammatory agents. The revised project contains a fourth aim, particularly targeting the mechanism of action for the minocycline treatment. The overall purpose of these studies is to investigate endogenous defense mechanisms as well as the degenerative process in itself, to explore if early intervention strategies can be employed.

R01AG012122

1994-04-08

2005-08-31