A new role for TMP21 in Alzheimer's Disease pathogenesis

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-β (Aβ) protein in neuritic plaques, and the formation of neurofibrillary tangles. Aβ is generated from a larger Aβ precursor protein (APP) following sequential cleavage by β- and γ-secretase. APP can also be cleaved in a non-amyloidogenic pathway following sequential cleavage by α- and γ-secretase. In addition to the pathogenic processing of APP, the γ-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 γ-secretase complex involved in AD pathogenesis. Knockdown of TMP21 increased Aβ production without affecting Notch cleavage, making it a seductive target for AD research.

This seminar will show that TMP21 is degraded by the ubiquitin-proteasome pathway, similar to other members of the γ-secretase complex, 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 α-secretase to β-secretase pathway in cell culture, and β-secretase and TMP21 could coimmunoprecipitate. This suggests that TMP21 may not only affect AD pathogenesis through its modulatory role on γ-secretase or its trafficking of APP, but also through its influence on β-secretase, providing a novel enzymatic target for future study.

Finally, this seminar 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 deficits in hippocampal learning and memory. This data will prove vital when examining future work regarding TMP21 suppression in a mouse model of AD.