Li H, Wang Z, Wang B, Guo Q, Dolios G, Tabuchi K, Hammer RE, Südhof TC, Wang R, Zheng H.
Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis.
J Biol Chem. 2010 Oct 1;285(40):30598-605.
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This interesting study from Hui Zheng’s lab shows that the cytosolic APP C-terminal domain is important for neuromuscular junction (NMJ) development and postnatal viability, but has no impact on brain β amyloid generation or deposition. To address the role of the APP C-terminus, knock-in animals (APP/hAβ/mutC) were generated by introducing an allele of APP695 bearing a human Aβ sequence with the Swedish/Arctic/London FAD mutations, and a frameshift mutation that results in a C-terminal truncated APP protein lacking the last 39 amino acids. Aβ40 and Aβ42 generation in young knock-in mice was not impaired and comparable to Aβ levels in APP/hAβ knock-in mice. Furthermore, Aβ deposition proceeded as expected in 13-month-old transgenic mice simultaneously bearing these alleles and a PS1M146V knock-in mutant allele. These data indicate that chronic expression of endogenous levels of this mutant protein in vivo does not result in trafficking defects that interfere with APPsα and Aβ generation. They also suggest that APP C-terminal post-translational modifications or interactions of APP with C-terminal binding proteins may only alter APP processing in response to specific cellular events.
To address the role of the APP C-terminus in other APP functions such as NMJ formation and postnatal viability, the authors crossed the APP/hAβ/mutC knock-in mice with APLP2 knockout mice to generate compound APP knock-in/APLP2 Knockout mice. Only 25 percent of the APP/hAβ/mutC knock-in/APLP2 KO mice survive to weaning age, and defects in NMJ morphology are found in diaphragm muscle of postnatal day zero (P0) pups. Since these mice only have a slight reduction in brain and spinal cord APP levels, and normal APPsα levels, it is unlikely that changes in APP levels contribute to the inability of the APP/hAβ/mutC knock-in allele to rescue viability and NMJ deficits. However, as pointed out by the authors in the discussion, defective APP trafficking may be the cause of these NMJ defects. The presence of only one of the two known APP C-terminal sorting motifs, YTSI, and the introduction of an additional 10 amino acids that are not normally found in APP may have altered sorting of this mutant APP protein to synapses. Furthermore, γ-secretase cleavage of the APP/hAβ/mutC allele will generate peptide fragments that are not normally present, and these may interfere with rescue. Support for the conclusion that the APP C-terminus is essential for NMJ formation and postnatal survival may come from analysis of these phenotypes in the progeny of crosses between mice bearing the APPsα knock-in (Ring et al., 2007) and the APLP2 knockout mice.
Ring S, Weyer SW, Kilian SB, Waldron E, Pietrzik CU, Filippov MA, Herms J, Buchholz C, Eckman CB, Korte M, Wolfer DP, Müller UC.
The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice.
J Neurosci. 2007 Jul 18;27(29):7817-26.