It is not only the abnormal product of amyloid precursor protein-the amyloid-beta peptide-that interests researchers of Alzheimer's disease. There is also a line of inquiry that hopes to find clues to the disease in the normal function of amyloid precursor protein (APP). To that end, a report in this month's Journal of Neuroscience demonstrates that APP and its close relatives, the amyloid precursor-like proteins (APLPs), have some overlapping functions, as well as serving some nonredundant, essential functions.
APP is found throughout the body, but its normal function is not yet established. Among the processes in which it has been implicated are neurite outgrowth, locomotor activity and grip strength, copper homeostasis, and susceptibility to epileptic seizures and excitotoxic agents. Because mice with their APP genes knocked out do survive (with minimal phenotypic changes), it has been theorized that the protein shares functions with the two structurally similar APLPs, (i.e., that deficits in one member of the family can be offset by the presence of the other proteins). This is supported by previous studies showing that APLP2 knockout mice also survive without obvious detriment, but that mice with both the APP and APLP2 genes knocked out die around the time of birth.
Ulrike Muller, Sabine Heber, and their colleagues now report that APLP1 knockout mice also survive and reproduce, apparently with only negligible phenotypic effects. The researchers confirmed that mice with both the APP and APLP2 genes knocked out do not survive and add evidence that the same is true for mice with both the APLP1 and APLP2 genes knocked out. Conversely, mice with their APP and APLP1 genes knocked out do not die, but appear phenotypically normal. Thus, it would seem that one family member is not enough, unless that member is APLP2. "These data indicate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2," write the authors.
None of the single or double mutants displayed any obvious histopathological abnormalities, even in the brain. Furthermore, none of the mutations, single or double, affected the ability of neurons to survive in vitro under normal culture conditions or increased their susceptibility to glutamate excitotoxicity. This last result runs counter to experimental evidence that APP and the APLPs might help protect neurons from the toxic effects of glutamate and Aβ peptide.—Hakon Heimer
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- Heber S, Herms J, Gajic V, Hainfellner J, Aguzzi A, Rülicke T, von Kretzschmar H, von Koch C, Sisodia S, Tremml P, Lipp HP, Wolfer DP, Müller U. Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci. 2000 Nov 1;20(21):7951-63. PubMed.