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Retromer Deficiency Observed in Alzheimer's Disease Causes Retromer deficiency observed in Alzheimer’s disease causes hippocampal dysfunction, neurodegeneration, and A␤ accumulation Alim Muhammad*, Ingrid Flores*, Hong Zhang*†, Rui Yu*, Agnieszka Staniszewski*†, Emmanuel Planel*†, Mathieu Herman*†, Lingling Ho‡, Robert Kreber‡, Lawrence S. Honig*§, Barry Ganetzky‡¶, Karen Duff*†, Ottavio Arancio*†, and Scott A. Small*§¶ *Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and Departments of §Neurology and †Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and ‡Laboratory of Genetics, University of Wisconsin, Madison, WI 53706-1580 Contributed by Barry Ganetzky, March 13, 2008 (sent for review December 2, 2007) Although deficiencies in the retromer sorting pathway have been ␥-secretase, it was important to investigate retromer deficiency linked to late-onset Alzheimer’s disease, whether these deficien- on a nonmutated genetic background. To determine whether cies underlie the disease remains unknown. Here we characterized retromer deficiency causes hippocampal dysfunction, a key two genetically modified animal models to test separate but clinical feature of Alzheimer’s disease, we began by investigating related questions about the effects that retromer deficiency has on retromer deficiency in genetically modified mice. Our results the brain. First, testing for cognitive defects, we investigated suggest that retromer deficiency causes hippocampal dysfunction retromer-deficient mice and found that they develop hippocampal- by elevating concentrations of endogenous A␤ peptide. dependent memory and synaptic dysfunction, which was associ- Although APP and BACE are highly homologous across species, ated with elevations in endogenous A␤ peptide. Second, testing important sequence differences do exist, and these differences can for neurodegeneration and amyloid deposits, we investigated affect their intracellular transport, APP processing, and the neu- retromer-deficient flies expressing human wild-type amyloid pre- rotoxicity of APP end products (12). Thus, guided by our first series cursor protein (APP) and human ␤-site APP-cleaving enzyme (BACE) of findings, it became important to investigate the effect that NEUROSCIENCE and found that they develop neuronal loss and human A␤ aggre- retromer deficiency has on a model brain expressing both human gates. By recapitulating features of the disease, these animal wild-type APP and human wild-type BACE. Exploiting the relative models suggest that retromer deficiency observed in late-onset ease of modifying the Drosophila genome, we turned to flies in our Alzheimer’s disease can contribute to disease pathogenesis. second series of studies, showing that retromer deficiency increases human A␤ levels and leads to neurodegeneration. flies ͉ mice ͉ pathophysiology Results n abnormal elevation in A␤ peptide is thought to represent Retromer Deficiency Causes Hippocampal-Dependent Memory and Aa neurotoxic agent in Alzheimer’s disease (1, 2). A␤ is Synaptic Dysfunction. A range of behavioral, imaging, and histolog- produced when its parent protein, the amyloid precursor protein ical studies have established that hippocampal dysfunction is a (APP), is sequentially cleaved by two enzymes, first by BACE dominant clinical feature of Alzheimer’s disease (13–15). To test (␤-site APP-cleaving enzyme) and then by the multimeric whether retromer deficiency causes hippocampal dysfunction we ␥-secretase. APP and BACE are transmembrane proteins, and examined genetically engineered mice. First, extending studies in in the last few years many of the molecular mechanisms that nonneuronal cell lines (7, 11), we performed coimmunoprecipita- regulate the sorting of APP and BACE through membrane tion experiments in extracts from mouse brain to show that sorLA compartments of the cell have been elucidated (3). Among these, and sortilin bind VPS35, confirming that they are neuronal retromer sorting is a pathway recently implicated in late-onset retromer-binding receptors (Fig. 1a). By exploring anatomical Alzheimer’s disease (LOAD) (4–7). First described in yeast, the expression maps (16), we find that genes related to the retromer retromer sorting pathway consists of a multimeric retromer complex, including VPS26 and VPS35, are highly and differentially complex—comprising VPS35, VPS26, VPS29, VPS5, and expressed in the hippocampal formation [supporting information VPS17—and retromer-binding receptors, in particular VPS10 (SI) Fig. S1]. In contrast, sortilin and sorLA are diffusely expressed (8) (Fig. 1a). Except for VPS17, mammalian homologues of the throughout the brain. This observation suggests that, within the retromer complex have been identified (9) and are expressed in retromer sorting pathway, molecules related to the retromer com- the brain among other tissue types. Mammals express a family of plex might confer hippocampal vulnerability. VPS10-containing molecules (10), and to date two members of To test this hypothesis, we investigated VPS26 heterozygote this family, sorLA (5, 7) and sortilin (11), have been shown to act knockout (KO) mice that, in contrast to homozygote KO mice, as retromer-binding receptors. survive into adulthood and do not manifest gross developmental Three lines of evidence have implicated the retromer sorting abnormalities (17). Western blot analysis confirmed that VPS26 pathway in LOAD. First, elements related to this pathway are deficient in the brains of LOAD patients, including VPS35, Author contributions: L.S.H., B.G., K.D., O.A., and S.A.S. designed research; A.M., I.F., H.Z., VPS26, and the VPS10-containing receptor sorLA (4). Second, R.Y., A.S., E.P., M.H., L.H., R.K., B.G., and S.A.S. performed research; S.A.S. contributed new down-regulating any of these three elements in cell culture reagents/analytic tools; A.M., L.H., B.G., K.D., and O.A. analyzed data; and B.G., K.D., O.A., causes abnormal elevation of A␤ (5, 7). Third, genetic variations and S.A.S. wrote the paper. in sorLA have been linked to LOAD (7). The authors declare no conflict of interest. Although implicated in LOAD, it is unknown whether defi- Freely available online through the PNAS open access option. ciencies in the retromer sorting pathway cause key features of the ¶To whom correspondence may be addressed. E-mail: [email protected] or sas68@ disease. We set out to address this issue by investigating two columbia.edu. retromer-deficient animal models, with each model addressing This article contains supporting information online at www.pnas.org/cgi/content/full/ separate but related questions. Because A␤ is produced in 0802545105/DCSupplemental. LOAD brains that express nonmutated APP, BACE, and © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0802545105 PNAS ͉ May 20, 2008 ͉ vol. 105 ͉ no. 20 ͉ 7327–7332 Downloaded by guest on September 26, 2021 a Retromer-Binding protein levels are reduced in the brains of the heterozygote KO receptor VPS10 mice (ϩ/Ϫ) compared with wild-type littermates (ϩ/ϩ) (five mice per group; t ϭ 4.1, P ϭ 0.001) (Fig. 1b). Furthermore, consistent V with previous studies (18) in which a primary reduction in VPS26 V P S 5 / ` 7 P S causes a secondary reduction in VPS35, VPS35 protein levels were VPS35 2 Retromer 9 also reduced in the brains of heterozygote KO mice (five mice per Complex group; t ϭ 2.9, P ϭ 0.01) (Fig. 1b). Thus, the retromer-deficient VPS26 state in the heterozygote KO mice is similar to that observed in the hippocampal formation of LOAD patients (5). Anti-sorLA Anti-sortilin To test for hippocampal-dependent memory deficits we used the VPS35 modified radial-arm maze, a behavioral task used to assess the VPS35 hippocampal formation in other mouse models of Alzheimer’s hom cont co-IP hom cont co-IP disease (19). Compared with wild-type littermates, the perfor- Anti-VPS35 Anti-VPS35 mance of the retromer-deficient mice was found to be defective [18 ϩ ϩ ϩ Ϫ sorLA sortilin / and 15 / mice; a multivariate test revealed a global effect (F ϭ 5.6, P ϭ 0.025) whereas univariate tests revealed that the effect hom cont co-IP hom cont co-IP was driven by defects at time 4 (P ϭ 0.014) and time 5 (P ϭ 0.001)] (Fig. 1c). In contrast, both heterozygous KO mice and wild-type b 1.2 VPS26 1.8 VPS35 mice performed similarly in a visible platform task indicating N or m alized levels sl l e v e e v e l s s 1.6 e v e l 1.6 normal motor, sensory, and motivational capabilities. 0.8 l N orm alized l d Memory defects observed in LOAD correlate with histolog- N orm alized e 1.4 zila 1.4 ical markers of hippocampal synaptic dysfunction (20), and a 0.4 m 1.2 ro 1.2 range of recent studies suggest that synaptic dysfunction is an N early hallmark of the disease (21, 22). Accordingly, we used 0 1 +/+WT +/-KO +/+WT +/-KO electrophysiological techniques to investigate hippocampal syn- aptic integrity of retromer-deficient mice. Compared with wild- +/+ +/- +/+ +/- type littermates, heterozygous KO mice were found to have VPS26 37KDa significant defects in long-term potentiation (18 ϩ/ϩ and 16 ϩ/Ϫ mice; F ϭ 5.1, P ϭ 0.025) (Fig. 1c) with preserved paired-pulse VPS35 91KDa facilitation and basal synaptic transmission. Actin 62KDa Retromer Deficiency Elevates Levels of Endogenous A␤ in the Mouse WT KO +/+ +/- Brain. The hippocampal-dependent memory dysfunction ob- served in LOAD correlates with elevated levels of soluble, not c 8 insoluble, forms of the A␤ peptide (21), and it is generally acknowledged that soluble forms of A␤ are neurotoxic. Com- 6 pared with wild-type littermates, heterozygous KO mice were E r r o r s found by ELISA to have elevated brain levels of endogenous 4 A␤40 (16 mice per group; F ϭ 11.4, P ϭ 0.002) and A␤42 (F ϭ 8.6, P ϭ 0.007) (Fig. 2a). No difference in the level of full-length 2 APP was observed (Fig.
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