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Li H, Wang B, Wang Z, Guo Q, Tabuchi K, Hammer RE, Südhof TC, Zheng H. Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17362-7. PubMed.
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The link between APP and Klotho is novel and very interesting. APP and Klotho share several common features: 1) They are single-pass transmembrane proteins with short intracellular domains; 2) they are substrates of α-, β-, and γ-secretases; 3) their extracellular domains are secreted and function as humoral factors.
Secreted Klotho has an activity that alleviates oxidative stress (Yamamoto et al., 2005) were reported to suffer cognitive impairment due to increased apoptosis of hippocampal neurons, which was rescued by administration of antioxidant (vitamin E) (Nagai et al., 2003).
Activation of BACE generates both Aβ and APPsβ. It will also facilitate secretion of Klotho. Thus, the ability of AAPsβ to increase Klotho expression may counteract harmful effects of Aβ by increasing secreted Klotho under the condition where BACE is activated. A major issue highlighted by this paper is a potential role of APP in the regulation of Klotho expression, the decline of which is known to occur with age (Duce et al., 2008) and to contribute to multiple age-related symptoms, including cognition impairment.
References:
Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu H, Miyoshi M, Ogawa Y, Castrillon DH, Rosenblatt KP, Kuro-O M. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem. 2005 Nov 11;280(45):38029-34. PubMed.
Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, Nabeshima T. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J. 2003 Jan;17(1):50-2. PubMed.
Duce JA, Podvin S, Hollander W, Kipling D, Rosene DL, Abraham CR. Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. Glia. 2008 Jan 1;56(1):106-17. PubMed.
Rutgers - New Jersey Medical School
This interesting paper from Hui Zheng’s lab reminds us that there is still much to learn about the normal function of the amyloid-β precursor protein (APP). Of course, it also reminds us that there is so little that we know for sure about what APP normally does. It should also remind us that the pathology in Alzheimer disease could come, at least in part, from the loss of function of APP. Finally, this paper reminds us that the APP fragments, generated by secretase cleavage in multiple cellular compartments, have functions of their own. This paper clearly shows that the fragments (in this case, sAPPβ) and full-length APP have non-overlapping functions. Moreover, the paper shows that APP and the fragments can have different functions during development and in the adult organism.
This paper does not address the problem of where the sAPPβ is normally generated, nor does it address how it is transported to the cell periphery, where it is eventually secreted. As we recently showed, all APP polypeptides, typically derived through secretase cleavage, are incorporated into transport vesicles and are independently targeted to distinct destinations, including axon terminals (1). We also proposed that, at these destinations, the fragments have functions that are independent of each other and of the parental APP molecule. The present paper adds to the list of functions of APP fragments. As someone recently said, “APP: many fragments, many roles.”
References:
Muresan V, Varvel NH, Lamb BT, Muresan Z. The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci. 2009 Mar 18;29(11):3565-78. PubMed.
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