The hAPP-YAC transgenic model has elevated UPS activity in the frontal cortex similar to Alzheimer's disease and Down's syndrome

The ubiquitin-proteasome system (UPS) is critical for handling the intra-cellular load of abnormal and misfolded proteins in several neurodegenerative diseases. First, to determine the effects of the over-expression of human amyloid precursor protein (hAPP) on UPS, we measured proteasome activities using fluorescent substrates in the frontal cortex of hAPP-yeast artificial chromosome (YAC) transgenic (tg) mice (R1.40, hemizygous; Lamb, Nat Genet, 9, 4; 1995). Chymotrypsin and PGPH-like activities of proteasome were increased in frontal cortex of hAPP-YAC tg mice. These proteasome activities (both chymotrypsin and PGPH-like) were further increased by cholinergic stimulation in littermate control mice, but not in hAPP-YAC tg mice. Nerve growth factor (NGF) levels were decreased by hAPP over-expression in the frontal cortex and hippocampus of hAPP-YAC tg mice, and further decreased by M1 agonist treatment in the hippocampus of littermate control and hAPP-YAC tg mice. Interestingly, the frontal cortex (BA9 area) of Alzheimer's disease (AD) patients (Stage 3, n=11) and Down's syndrome (DS) patients (n=9) showed similar up-regulation of the UPS activities to those seen in hAPP-YAC tg mice. M1 agonist stimulation increased the activities of α-secretase, which were down-regulated by hAPP over-expression in the frontal cortex of hAPP-YAC tg mice. These results demonstrate that (i) hAPP-YAC tg mice have an up-regulation in the frontal cortex of the UPS similar to AD and DS patients; (ii) muscarinic stimulation increase UPS activities, increase secreted APP (APPs) levels, and decrease amyloid beta 42/40 ratio only in littermate controls, but not in hAPP-YAC tg mice. Taken together, these results suggest that both the adaptive reactions in the proteostatic network and pathological changes in AD and DS need to be considered in the future potential therapeutics.