What the evolution of the amyloid protein precursor supergene family tells us about its function

Coulson, Elizabeth J.; Paliga, Krzysztof; Beyreuther, Konrad; Masters, CL

doi:10.1016/s0197-0186(99)00125-4

Cited by 195 publications

(170 citation statements)

References 82 publications

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“…APLP-2 undergoes a processing more extensive and more similar to that of APP, also including ␤-like cleavages. This might be expected, since APP and APLP-2 are evolutionarily more closely related to each other than to APLP-1, which represents the ancestral form of the APP gene family members (2). Our findings suggest that despite some differences in the processing of the members of the APP gene family, future treatment of patients with Alzheimer's disease by modulation of APP processing should take into consideration the effect on APLP-1 and APLP-2 processing.…”

Section: Discussionmentioning

confidence: 67%

“…APP is a member of a multigene family comprising at least 16 orthologues (2) that encode type I integral membrane proteins with similar multidomain structures (reviewed in Ref. 2). There are two mammalian APP homologues, the APP-like proteins, termed APLP-1 (3,4) and APLP-2 (5, 6), which share similar domain structures with APP (reviewed in Ref.…”

mentioning

confidence: 99%

“…There are two mammalian APP homologues, the APP-like proteins, termed APLP-1 (3,4) and APLP-2 (5, 6), which share similar domain structures with APP (reviewed in Ref. 2). Transgenic mice with single knock-out of either the APP (7), APLP-1 (8), or APLP-2 (9) gene show no severe phenotype, suggesting that the mammalian APP gene family members have a redundant function.…”

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confidence: 99%

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The Proteolytic Processing of the Amyloid Precursor Protein Gene Family Members APLP-1 and APLP-2 Involves α-, β-, γ-, and ϵ-Like Cleavages

Eggert

Paliga

Soba

et al. 2004

Journal of Biological Chemistry

199

189

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Amyloid precursor protein (APP) processing is of major interest in Alzheimer's disease research, since sequential cleavages by ␤-and ␥-secretase lead to the formation of the 4-kDa amyloid A␤ protein peptide that accumulates in Alzheimer's disease brain. The processing of APP involves proteolytic conversion by different secretases leading to ␣-, ␤-, ␥-, ␦-, and ⑀-cleavages. Since modulation of these cleavages represents a rational therapeutic approach to control amyloid formation, its interference with the processing of the members of the APP gene family is of considerable importance. By using C-terminally tagged constructs of APLP-1 and APLP-2 and the untagged proteins, we have characterized their proteolytic C-terminal fragments produced in stably transfected SH-SY5Y cells. Pharmacological manipulation with specific protease inhibitors revealed that both homologues are processed by ␣-and ␥-secretase-like cleavages, and that their intracellular domains can be released by cleavage at ⑀-sites. APLP-2 processing appears to be the most elaborate and to involve alternative cleavage sites. We show that APLP-1 is the only member of the APP gene family for which processing can be influenced by N-glycosylation. Additionally, we were able to detect p3-like fragments of APLP-1 and p3-like and A␤-like fragments of APLP-2 in the media of stably transfected SH-SY5Y cells.

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Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Proteolytic Processing of the Amyloid Precursor Protein Gene Family Members APLP-1 and APLP-2 Involves α-, β-, γ-, and ϵ-Like Cleavages

Eggert

Paliga

Soba

et al. 2004

Journal of Biological Chemistry

199

189

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“…Nonetheless, as noted above, the 42-amino acid sequence of Aβ is identical in human, great ape, and monkey (Johnstone et al 1991). With remarkably few exceptions (lab rodents), the Aβ sequence is identical in other vertebrates, including zebra fish (Coulson et al 2000). The absence of diffuse Aβ plaques in old lab rodents may be attributed to three amino acid differences that slow aggregation (Boyd-Kimball et al 2004).…”

Section: Species Differences In Relevant Genesmentioning

confidence: 98%

Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging

Finch

Austad²

2012

AGE

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At later ages, humans have high risk of developing Alzheimer disease (AD) which may afflict up to 50% by 90 years. While prosimians and monkeys show more substantial changes, the great apes brains examined show mild neurodegenerative changes. Compared with rodents, primates develop and reproduce slowly and are long lived. The New World primates contain some of the shortest as well as some of the longest-lived monkey species, while the prosimians develop the most rapidly and are the shortest lived. Great apes have the largest brains, slowest development, and longest lives among the primates. All primates share some level of slowly progressive, age-related neurodegenerative changes. However, no species besides humans has yet shown regular drastic neuron loss or cognitive decline approaching clinical grade AD. Several primates accumulate extensive deposits of diffuse amyloid-beta protein (Aβ) but only a prosimian-the gray mouse lemur-regularly develops a tauopathy approaching the neurofibrillary tangles of AD. Compared with monkeys, nonhuman great apes display even milder brain-aging changes, a deeply puzzling observation. The genetic basis for these major species differences in brain aging remains obscure but does not involve the Aβ coding sequence which is identical in nonhuman primates and humans. While chimpanzees merit more study, we note the value of smaller, shorterlived species such as marmosets and small lemurs for aging studies. A continuing concern for all aging studies employing primates is that relative to laboratory rodents, primate husbandry is in a relatively primitive state, and better husbandry to control infections and obesity is needed for brain aging research.

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“…Alternative splicing of the APP gene produces three major isoforms (695aa, 751aa, and 770aa), with APP 695 being the major form found in the nervous system (Tanaka et al, 1989;Lorent et al, 1995). In addition to APP, vertebrates express two closely related proteins called Amyloid Precursor-Like Proteins (APLP) 1 and 2 (Coulson et al, 2000;Turner et al, 2003).…”

mentioning

confidence: 99%

Analysis of amyloid precursor protein function in Drosophila melanogaster

2011

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The Amyloid precursor protein (APP) has mainly been investigated in connection with its role in Alzheimer's Disease (AD) due to its cleavage resulting in the production of the Aβ peptides that accumulate in the plaques characteristic for this disease. However, APP is an evolutionary conserved protein that is not only found in humans but also in many other species, including Drosophila, suggesting an important physiological function. Besides Aβ, several other fragments are produced by the cleavage of APP; large secreted fragments derived from the N-terminus and a small intracellular C-terminal fragment. Although these fragments have received much less attention than Aβ, a picture about their function is finally emerging. In contrast to mammals, which express three APP family members, Drosophila expresses only one APP protein called APP-like or APPL. Therefore APPL functions can be studied in flies without the complication that other APP family members may have redundant functions. Flies lacking APPL are viable but show defects in neuronal outgrowth in the central and peripheral nervous system (PNS) in addition to synaptic changes. Furthermore, APPL has been connected with axonal transport functions. In the adult nervous system, APPL, and more specifically its secreted fragments, can protect neurons from degeneration. APPL cleavage also prevents glial death. Lastly, APPL was found to be involved in behavioral deficits and in regulating sleep/activity patterns. This review, will describe the role of APPL in neuronal development and maintenance and briefly touch on its emerging function in circadian rhythms while an accompanying review will focus on its role in learning and memory formation.

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What the evolution of the amyloid protein precursor supergene family tells us about its function

Cited by 195 publications

References 82 publications

The Proteolytic Processing of the Amyloid Precursor Protein Gene Family Members APLP-1 and APLP-2 Involves α-, β-, γ-, and ϵ-Like Cleavages

The Proteolytic Processing of the Amyloid Precursor Protein Gene Family Members APLP-1 and APLP-2 Involves α-, β-, γ-, and ϵ-Like Cleavages

Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging

Analysis of amyloid precursor protein function in Drosophila melanogaster

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