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Many neurodegenerative diseases are characterized by deposits of ubiquitinated and aberrant proteins, suggesting a failure of the ubiquitin-proteasome system (UPS). The aberrant ubiquitin UBB(+1) is one of the ubiquitinated proteins accumulating in tauopathies such as Alzheimer's disease (AD) and polyglutamine diseases such as Huntington's disease. We have generated UBB(+1) transgenic mouse lines with post-natal neuronal expression of UBB(+1), resulting in increased levels of ubiquitinated proteins in the cortex. Moreover, by proteomic analysis, we identified expression changes in proteins involved in energy metabolism or organization of the cytoskeleton. These changes show a striking resemblance to the proteomic profiles of both AD brain and several AD mouse models. Moreover, UBB(+1) transgenic mice show a deficit in contextual memory in both water maze and fear conditioning paradigms. Although UBB(+1) partially inhibits the UPS in the cortex, these mice do not have an overt neurological phenotype. These mouse models do not replicate the full spectrum of AD-related changes, yet provide a tool to understand how the UPS is involved in AD pathological changes and in memory formation.

Biomarkers present in the cerebrospinal fluid (CSF) of Alzheimer Disease patients could be instrumental in guiding diagnosis and monitoring of progression of the disease. We have previously reported on the secretion of a frameshifted form of amyloid-beta precursor protein, APP+1, into the CSF of Alzheimer patients and controls. APP+1 is secreted efficiently in controls, but during the progression of Alzheimer Disease, its secretion is reduced and APP+1 accumulates in tangle-bearing neurons. Here we describe the generation of a transgenic mouse line expressing APP+1 in the brain. These mice do not suffer from overt pathology or neurodegeneration, suggesting that APP+1 is not neurotoxic. To measure APP+1 levels in the CSF, we serially sampled CSF from the cisterna magna in the same mouse over a period of months. Indeed, APP+1 is secreted into the CSF of the transgenic mice, and APP+1 levels are stable over 1 year. This mouse model may guide the study of secretion deficits as found in Alzheimer Disease.