UBC Theses and Dissertations
Roles of TMP21 in Alzheimer's disease Zhang, Xiaojie
Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological feature of Alzheimer’s disease (AD). Aβ is derived from the cleavages of amyloid β precursor protein (APP) by β-secretase at Asp-1 site and by γ-secretase. Beta-site APP cleaving enzyme 1 (BACE1) is the β-secretase. It mainly cleaves APP within the Aβ region at the Glu-11 site to generate truncated Aβ species. Twenty-one kilodalton transmembrane trafficking protein, TMP21 (also named TMED10, p23) is a vesicular trafficking protein and a member of p24 family proteins. TMP21 mediates protein endoplasmic reticulum (ER)/Golgi transport and selectively guides the glycosylphosphatidylinositol-anchored proteins into lipid rafts. It is also essential for forming Golgi structural organization. Recent studies show that the downregulation of TMP21 increases Aβ generation by affecting APP trafficking and selectively modulating γ-cleavage on APP. However, the precise roles of TMP21 in AD pathogenesis remain unknown. In this thesis, we reported the discovery of a novel AD-associated single nucleotide polymorphism (SNP) in the intron 4 of Tmp21. This SNP significantly increases TMP21 transcript splicing efficiency in vitro, resulting in upregulation of TMP21 gene expression. Furthermore, we found that overexpression of TMP21 shifts APP processing from the non-amyloidogenic to the amyloidogenic pathway by specifically increasing the BACE1 activity at Asp-1 site. Downregulation of TMP21 also facilitates amyloidogenic cleavage. The interaction between TMP21 and BACE1 is essential for BACE1’s ER export, and TMP21 enhances APP/BACE1 co-residency and might guide both APP and immature BACE1 in lipid rafts-like structures. In summary, this study defined the roles of TMP21 in AD pathogenesis. It demonstrated for the first time the genetic association between TMP21 and AD. The study also found that TMP21 facilitates APP amyloidogenic processing by modulating BACE1 maturation and trafficking, leading to increased BACE1 cleavage at Asp-1 site to generate Aβ. Therefore, interrupting the interaction between TMP21 and BACE1 to reduce Aβ production could be potential strategy to develop drugs for treating AD.
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