Acta Neuropathologica

, Volume 125, Issue 4, pp 535–547 | Cite as

Brain regional correlation of amyloid-β with synapses and apolipoprotein E in non-demented individuals: potential mechanisms underlying regional vulnerability to amyloid-β accumulation

  • Mitsuru Shinohara
  • Ronald C. Petersen
  • Dennis W. Dickson
  • Guojun Bu
Original Paper

Abstract

To reveal the underlying mechanisms responsible for the regional vulnerability to amyloid-β (Aβ) accumulation prior to the development of Alzheimer’s disease, we studied distribution of Aβ, apolipoprotein E (apoE), synaptic markers, and other molecules involved in Aβ metabolism in multiple brain areas of non-demented individuals. Twelve brain regions including neocortical, limbic, and subcortical areas were dissected from brains of non-demented individuals and extracted according to increasing insolubility by a sequential three-step method. The levels of Aβ40, Aβ42, apoE, APP, APP-CTFβ, BACE1, presenilin-1, neprilysin, insulysin, LRP1, LDLR, synaptophysin, PSD95, GFAP, and lactate were determined by ELISAs or enzymatic assays. The regional distribution of apoE showed moderate-to-strong inverse correlation with levels of Aβ, especially insoluble Aβ40. On the other hand, the regional distributions of synaptic markers, particularly PSD95, showed moderate-to-strong positive correlation with levels of Aβ, especially soluble Aβ40. The regional correlations between Aβ and LRP1, GFAP, or lactate were mild-to-moderate. Moderate-to-strong positive regional correlations were observed between apoE and GFAP or lactate and between PSD95 and LRP1. No significant regional correlations were detected between Aβ and APP, APP-CTFβ, BACE1, or presenilin-1, those involved in Aβ production. There were no significant negative regional correlations between Aβ and two major Aβ degrading enzymes, neprilysin and insulysin. These regional correlations remained consistent regardless of the degree of Aβ accumulation. The regional vulnerability to Aβ accumulation may be due to a net balance between two competing processes: (1) synapses involved in promoting the initial Aβ accumulation and (2) astrocyte-derived apoE involved in preventing Aβ accumulation.

Keywords:

Alzheimer’s disease Amyloid-β Regional vulnerability Apolipoprotein E Synapses 

Notes

Acknowledgments

We thank Dr. Pritam Das for ELISA reagents detecting Aβ and an antibody against C-terminus region of APP, Drs. Malcolm Leissring and Samir Abdul-Hay for ELISA reagents detecting IDE, Mr. John Gonzalez for assisting with dissection of brain tissues, Ms. Caroline Stetler for careful reading of this manuscript, and Dr. Takahisa Kanekiyo for helpful discussion. This research was supported by grants from the National Institutes of Health (NIH) (P01 AG030128-Project 3 & P01 NS074969-Project 3 to G.B.); Alzheimer’s Drug Discovery Foundation (ADDF) (to G.B.); American Health Assistance Foundation (AHAF) (to G.B.); Mayo Clinic Alzheimer’s Disease Research Center (ADRC) (P50 AG016574) (to D.W.D and M.S.); Japan Heart Foundation and Naito Foundation (to M.S.). The authors also acknowledge the many individuals who contribute to the Mayo Clinic Alzheimer Disease Research Center (PI: R.C.P., P50 AG016574) and Mayo Clinic Study on Aging (PI: R.C.P., U01 AG006786), as well as the neuropathology core in Rochester, MN (Dr. Joseph Parisi), without whose contributions this study would not have been possible.

Conflict of interest

R.C.P. has been chair of a safety monitoring committee for Pfizer (Wyeth) and Janssen Alzheimer Immunotherapy (Elan); and a consultant for Elan Pharmaceuticals and GE Healthcare. All other authors declare that they have no conflicts of interest.

Supplementary material

401_2013_1086_MOESM1_ESM.docx (6.7 mb)
Supplementary material 1 (DOCX 6872 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Mitsuru Shinohara
    • 1
  • Ronald C. Petersen
    • 2
  • Dennis W. Dickson
    • 1
  • Guojun Bu
    • 1
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Department of NeurologyMayo ClinicRochesterUSA

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