Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease

Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-β (Aβ) in vitro. To determine whether endogenous clusterin plays a role in influencing Aβ deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin−/− mice. By 12 months of age, PDAPP, clusterin−/− mice had similar levels of brain Aβ deposition as did PDAPP, clusterin+/+ mice. Although Aβ deposition was similar, PDAPP, clusterin−/− mice had significantly fewer fibrillar Aβ (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Aβ structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.

[1]  Dominic M. Walsh,et al.  Protofibrillar Intermediates of Amyloid β-Protein Induce Acute Electrophysiological Changes and Progressive Neurotoxicity in Cortical Neurons , 1999, The Journal of Neuroscience.

[2]  S. Paul,et al.  Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition , 1997, Nature Genetics.

[3]  S. Greenberg,et al.  Pathogenic Effects of D23N Iowa Mutant Amyloid β-Protein* , 2001, The Journal of Biological Chemistry.

[4]  J. Carver,et al.  Clusterin Has Chaperone-like Activity Similar to That of Small Heat Shock Proteins* , 1999, The Journal of Biological Chemistry.

[5]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Holtzman,et al.  Nascent Astrocyte Particles Differ from Lipoproteins in CSF , 1998, Journal of neurochemistry.

[7]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[8]  C. Brown,et al.  Clusterin, a binding protein with a molten globule-like region. , 2001, Biochemistry.

[9]  A Rostagno,et al.  Apolipoprotein J (clusterin) and Alzheimer's disease , 2000, Microscopy research and technique.

[10]  C. Finch,et al.  Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? , 2001, Trends in Neurosciences.

[11]  P. May,et al.  Clusterin (Apo J) Protects Against In Vitro Amyloid‐β(1–40) Neurotoxicity , 1996 .

[12]  D. Holtzman,et al.  Clusterin contributes to caspase-3–independent brain injury following neonatal hypoxia-ischemia , 2001, Nature Medicine.

[13]  G. Vega,et al.  Apolipoproteins in human cerebrospinal fluid. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. Motter,et al.  Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease , 1997 .

[15]  R. James,et al.  Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid. , 1995, Biochimica et biophysica acta.

[16]  S. Younkin,et al.  The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation , 2001, Nature Neuroscience.

[17]  T. Wisniewski,et al.  Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer's amyloid beta. , 1994, Biochemical and biophysical research communications.

[18]  B. Aronow,et al.  Apolipoprotein J expression at fluid-tissue interfaces: potential role in barrier cytoprotection. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Steven A. Johnson,et al.  Clusterin (apoJ) Alters the Aggregation of Amyloid β-Peptide (Aβ1-42) and Forms Slowly Sedimenting Aβ Complexes That Cause Oxidative Stress , 1995, Experimental Neurology.

[20]  C. Finch,et al.  Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration , 1992, Trends in Neurosciences.

[21]  C. Soto,et al.  Apolipoprotein J and Alzheimer's amyloid beta solubility. , 1996, The Biochemical journal.

[22]  E. Matsubara,et al.  Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Wisniewski,et al.  The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. , 1993, The Biochemical journal.

[24]  E. Matsubara,et al.  Characterization of Apolipoprotein J-Alzheimer's Aβ Interaction (*) , 1995, The Journal of Biological Chemistry.

[25]  David J. Cummins,et al.  Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[26]  S. Sisodia.  Alzheimer's disease: perspectives for the new millennium. , 1999, The Journal of clinical investigation.

[27]  Brett Chromy,et al.  Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus , 2002, Brain Research.

[28]  B. Aronow,et al.  Apolipoprotein J/clusterin limits the severity of murine autoimmune myocarditis. , 2000, The Journal of clinical investigation.

[29]  S. Ranganathan,et al.  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. , 1997, The Journal of biological chemistry.

[30]  L. Mucke,et al.  Comparison of Neurodegenerative Pathology in Transgenic Mice Overexpressing V717F β-Amyloid Precursor Protein and Alzheimer’s Disease , 1996, The Journal of Neuroscience.

[31]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[32]  S. Paul,et al.  Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A. Fagan,et al.  Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model , 2000, Annals of neurology.

[34]  J. Carver,et al.  Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. , 2000, Biochemistry.

[35]  Xianlin Han,et al.  Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice , 2001, Neurochemistry International.

[36]  J. Olney,et al.  MK-801 neurotoxicity in male mice: histologic effects and chronic impairment in spatial learning , 1996, Brain Research.

[37]  T. Wisniewski,et al.  Biology of Aβ Amyloid in Alzheimer's Disease , 1997, Neurobiology of Disease.

[38]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[39]  W. H. Jordan,et al.  Statistical aspects of quantitative image analysis of β-amyloid in the APPV717F transgenic mouse model of Alzheimer's disease , 2001, Journal of Neuroscience Methods.

[40]  A. Fagan,et al.  Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Steven A. Johnson,et al.  Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat , 1990, Neuron.