Association of apolipoprotein J-positive β-amyloid plaques with dystrophic neurites in alzheimer’s disease brain
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Apolipoprotein J (apoJ), also known as clusterin and SP-40,40, binds soluble beta-amyloid (Aβ and is up-regulated in the Alzheimer’s disease (AD) brain. In the present study we classified apoJ-immunopositive Aβ deposits in AD temporal cortex, and found apoJ-immunoreactive plaques were often associated with dystrophic neurites. Quantitative immunohistochemical analysis of five AD brains showed that 29% of Aβ deposited in the parenchyma was associated with apoJ. Of Aβ deposits with apoJ immunopositivity, 71% were associated with phospho-tau-positive dystrophic neurites in the surrounding tissue. Conversely, 64% of phospho-tau-labeled neuritic deposits were labeled with apoJ. ApoJ was found at the core of these deposits, and co-localized with the amyloid staining agent thioflavine-S. To test the direct effects of apoJ on tau metabolism, we treated cells in culture with apoJ-containing conditioned media, and we injected apoJ-containing media into the rat hippocampus. Using both systems, we observed increases in levels of tau and phosphorylated tau. Our findings demonstrate that apoJ immunopositivity strongly correlates with the presence of amyloid and associated neuritic dystrophy in the neuropil of AD temporal cortex, and supports a model where extracellular apoJ facilitates the conversion of diffuse Aβ deposits into amyloid and enhances tau phosphorylation in neurites surrounding these plaques.
KeywordsClusterin Immunofluorescence SP-40,40 Tau
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- Bales KR, T Verina, DJ Cummins, Y Du, RC Dodel, J Saura, CE Fishman, CA DeLong, P Piccardo, V Petegnief, B Ghetti and SM Paul (1999) Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer’s disease.Proc. Natl. Acad. Sci. USA 96, 15233–15238.PubMedCrossRefGoogle Scholar
- DeMattos RB, MA O’Dell, M Parsadanian, JW Taylor, JAK Harmony, KR Bales, SM Paul, BJ Aronow and DM Holtzman (2002) Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model for Alzheimer’s disease.Proc. Natl. Acad. Sci. USA 99, 10843–10848.PubMedCrossRefGoogle Scholar
- Ghiso J, E Matsubara, A Koudinov, NH Choi-Miura, M Tomita, T Wisniewski and B Frangione (1993) The cerebrospinal fluid soluble form of Alzheimer’s amyloid beta is complexed to SP40,40 (apolipoprotein J), an inhibitor of the complement membrane attack complex.Biochem. J. 293, 27–30.PubMedGoogle Scholar
- Hammad SM, S Ranganathan, E Loukinova, WO Twal and WS Argraves (1997) Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide.J. Biol. Chem. 272, 18644–18649.PubMedCrossRefGoogle Scholar
- Holtzman DM, KR Bales, T Tenkova, AM Fagan, M Parsadanian, LJ Sartorius, B Mackey, J Olney, D McKeel, D Wozniak and SM Paul (2000a) Apolipoprotein E isoform-dependant amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease.Proc. Natl. Acad. Sci. USA 97, 2892–2897.PubMedCrossRefGoogle Scholar
- Paxinos G and C Watson (1997)The Rat Brain in Stereotaxic Coordinates (Academic Press: New York).Google Scholar
- Qiu Z, Strickland DK, Hyman BT, and GW Rebeck (2002) ?2-Macroglobulin exposure reduces calcium responses toN-methyl-D-aspartate via low density lipoprotein recepor-related protein in cultured hippocampal neurons.J. Biol. Chem. 277, 14459–14466.Google Scholar
- Scheuner D, C Eckman, M Jensen, X Song, M Citron, N Suzuki, TD Bird, J Hardy, M Hutton, W Kukull, E Larson, E Levy-Lahad, M Viitanen, E Peskind, P Poorkaj, G Schellenberg, R Tanzi, W Wasco, L Lannfelt, D Selkoe and S Younkin (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increasedin vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease.Nat. Med. 2, 850–852.CrossRefGoogle Scholar
- Stoltzner SE, TJ Grenfell, C Mori, KE Wisniewski, TM Wisniewski, DJ Selkoe and CA Lemere (2002) Temporal accrual of complement proteins in amyloid plaques in Down’s syndrome with Alzheimer’s disease.Am. J. Pathol. 156, 489–499.Google Scholar