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TMP21 in Alzheimer's disease : biochemical and behavioural characterization of TMP21 Bromley-Brits, Kelley

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia. The two major neuropathological hallmarks of AD are the deposition of amyloid-b (Ab) protein in neuritic plaques and the formation of neuro brillary tangles. Ab is generated from a larger Ab recursor protein (APP) following sequential cleavage by b- and g-secretase. APP can also be cleaved in a non-amyloidogenic pathway following sequential cleavage by a- and g-secretase. In addition to the pathogenic processing of APP, the g-secretase complex also cleaves a protein called Notch, which is essential for embryonic development and may be involved in learning and memory. Transmembrane emp24-like trafficking protein 10 (TMP21) is a 21 kDa transmembrane protein involved in vesicular trafficking. Ubiquitously expressed, particularly in the plasma membrane, endoplasmic reticulum, and Golgi, TMP is vital to development, and homozygous knockout mice are embryonic lethal. Recently, TMP21 was found to play a second, pivotal role as a regulatory member of the g-secretase complex involved in AD pathogenesis. Knockdown of TMP21 increased Ab production without affecting Notch cleavage, making it a seductive target for AD research (Chen et al., 2006). This thesis shows that, similar to other members of the g-secretase complex, TMP21 is also degraded by the ubiquitin-proteasome pathway, as treatment with proteasomal inhibitors increased TMP21 protein levels in both a time- and dose-dependent manner. Furthermore, overexpression of TMP21 shifted APP processing from the a-secretase to b-secretase pathway in cell culture, and b-secretase and TMP21 could coimmunoprecipitate. This suggests that TMP21 may not only a ffect AD pathogenesis through its modulatory role on g-secretase or its trafficking of APP (Vetrivel et al., 2007), but also through its influence on b-secretase, providing a novel enzymatic target for future study. Finally, this work presents the only in vivo study of the behavioural consequences of TMP21 suppression. Motor function, anxiety, and learning and memory were examined using a comprehensive test battery. Mice heterozygous for TMP21 were found to have slightly enhanced physical abilities, increased anxiety, and potential anxiety-augmented de ficits in hippocampal learning and memory. This data will prove vital when examining future work regarding TMP21 suppression in a mouse model of AD.

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