Origins of Beta Amyloid Differ Between Vascular Amyloid Deposition and Parenchymal Amyloid Plaques in the Spinal Cord of a Mouse Model of Alzheimer’s Disease

Abstract

Cerebral amyloid angiopathy (CAA) refers to pathological changes occurring in cerebral blood vessels caused by deposition of beta amyloid (Aβ) protein. However, the mechanisms involved in the origin of Aβ for the formation of CAA and its link to parenchymal amyloid depositions remained to be unraveled. Here, we found CAA and parenchymal plaques distributed separately instead of mingling with each other in the spinal cord of TgCRND8 mice. Parenchymal plaques predominantly located in the dorsal horn whereas CAA distributed in the ventral horn. We further found that the ratio of Aβ40/Aβ42 was significantly higher in the ventral than that in the dorsal by ELISA assay, suggesting that origin of Aβ forming parenchymal plaques may be different from that of CAA in the spinal cord. This hypothesis was further demonstrated by the surgical methods which indicated eliminating parenchymal plaques did not alter CAA in the affected spinal cord. We also examined the ratio of Aβ40/Aβ42 in the cerebral spinal fluid (CSF) in order to identify the origin of the CAA formation, and found the Aβ40/Aβ42 ratio was similar to that of CAA formation in the ventral horn. We further demonstrated that CSF tracer distributed along ventral horn vessels, in exactly the same pattern as Aβ deposition in CAA in ventral part of spinal cord. These findings verified the concept that CSF influx may act as a constant source for delivering Aβ, and contribute to the growth of paraarterial deposits in CAA. Taken together, the results of the present study highlight the important role of the Aβ40/Aβ42 ratio in determining vascular versus parenchymal amyloid deposition. Unlike parenchymal plaques, Aβ of CAA comes from CSF; thus, manipulation of CSF Aβ could represent a novel strategy to treat CAA.

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Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. 1.

    Davis J, Van Nostrand WE (1996) Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein. Proc Natl Acad Sci U S A 93(7):2996–3000

    CAS  Article  Google Scholar 

  2. 2.

    Wisniewski T, Ghiso J, Frangione B (1991) Peptides homologous to the amyloid protein of Alzheimer’s disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Commun 179(3):1247–1254

    CAS  Article  Google Scholar 

  3. 3.

    Verbeek MM, de Waal RM, Schipper JJ, Van Nostrand WE (1997) Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem 68(3):1135–1141

    CAS  Article  Google Scholar 

  4. 4.

    Yamamoto N, Hirabayashi Y, Amari M, Yamaguchi H, Romanov G, Van Nostrand WE, Yanagisawa K (2005) Assembly of hereditary amyloid beta-protein variants in the presence of favorable gangliosides. FEBS Lett 579(10):2185–2190

    CAS  Article  Google Scholar 

  5. 5.

    Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM (2005) Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci 25(11):2803–2810

    CAS  Article  Google Scholar 

  6. 6.

    Herzig MC, Van Nostrand WE, Jucker M (2006) Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models. Brain Pathol 16(1):40–54

    CAS  Article  Google Scholar 

  7. 7.

    Herzig MC, Paganetti P, Staufenbiel M, Jucker M (2007) BACE1 and mutated presenilin-1 differently modulate Abeta40 and Abeta42 levels and cerebral amyloidosis in APPDutch transgenic mice. Neurodegener Dis 4(2–3):127–135

    CAS  Article  Google Scholar 

  8. 8.

    Wojtas AM, Kang SS, Olley BM, Gatherer M, Shinohara M, Lozano PA, Liu CC, Kurti A et al (2017) Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Proc Natl Acad Sci U S A 114(33):E6962–E6971

    CAS  Article  Google Scholar 

  9. 9.

    Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C et al (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci U S A 96(24):14088–14093

    CAS  Article  Google Scholar 

  10. 10.

    Albargothy NJ, Johnston DA, MacGregor-Sharp M, Weller RO, Verma A, Hawkes CA, Carare RO (2018) Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathol 136(1):139–152

    CAS  Article  Google Scholar 

  11. 11.

    Carare RO (2017) Editorial: clearance pathways for amyloid-beta. Significance for Alzheimer’s disease and its therapy. Front Aging Neurosci 9:339

    Article  Google Scholar 

  12. 12.

    Carare RO, Hawkes CA, Jeffrey M, Kalaria RN, Weller RO (2013) Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol 39(6):593–611

    CAS  Article  Google Scholar 

  13. 13.

    Criswell TP, Sharp MM, Dobson H, Finucane C, Weller RO, Verma A, Carare RO (2017) The structure of the perivascular compartment in the old canine brain: a case study. Clin Sci (Lond) 131(22):2737–2744

    Article  Google Scholar 

  14. 14.

    Hawkes CA, Hartig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, Carare RO (2011) Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol 121(4):431–443

    Article  Google Scholar 

  15. 15.

    Hawkes CA, Jayakody N, Johnston DA, Bechmann I, Carare RO (2014) Failure of perivascular drainage of beta-amyloid in cerebral amyloid angiopathy. Brain Pathol 24(4):396–403

    CAS  Article  Google Scholar 

  16. 16.

    Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D et al (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7(9):954–960

    CAS  Article  Google Scholar 

  17. 17.

    Nedergaard M (2013) Neuroscience. Garbage truck of the brain. Science 340(6140):1529–1530

    CAS  Article  Google Scholar 

  18. 18.

    Sancesario GM, Bernardini S (2018) Diagnosis of neurodegenerative dementia: where do we stand, now? Ann Transl Med 6(17):340

    Article  Google Scholar 

  19. 19.

    Lehmann S, Delaby C, Boursier G, Catteau C, Ginestet N, Tiers L, Maceski A, Navucet S et al (2018) Relevance of Abeta42/40 ratio for detection of Alzheimer disease pathology in clinical routine: the PLMR scale. Front Aging Neurosci 10:138

    Article  Google Scholar 

  20. 20.

    Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H (2013) Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 123(3):1299–1309

    CAS  Article  Google Scholar 

  21. 21.

    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4(147):147ra111

    Article  Google Scholar 

  22. 22.

    Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N et al (2001) Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276(24):21562–21570

    CAS  Article  Google Scholar 

  23. 23.

    Janus C, Phinney AL, Chishti MA, Westaway D (2001) New developments in animal models of Alzheimer’s disease. Curr Neurol Neurosci Rep 1(5):451–457

    CAS  Article  Google Scholar 

  24. 24.

    Yuan Q, Su H, Chau WH, Toa Ng C, Huang JD, Wu W, Lin ZX (2013) Behavioral stress fails to accelerate the onset and progression of plaque pathology in the brain of a mouse model of Alzheimer’s disease. PLoS One 8(1):e53480

    CAS  Article  Google Scholar 

  25. 25.

    Yuan Q, Su H, Zhang Y, Chau WH, Ng CT, Song YQ, Huang JD, Wu W et al (2013) Amyloid pathology in spinal cord of the transgenic Alzheimer’s disease mice is correlated to the corticospinal tract pathway. J Alzheimers Dis 35(4):675–685

    Article  Google Scholar 

  26. 26.

    Yuan Q, Su H, Zhang Y, Chau WH, Ng CT, Wu W, Lin ZX (2013) Existence of different types of senile plaques between brain and spinal cord of TgCRND8 mice. Neurochem Int 62(3):211–220

    CAS  Article  Google Scholar 

  27. 27.

    Yuan Q, Yang J, Wu W, Lin ZX (2017) Motor deficits are independent of axonopathy in an Alzheimer’s disease mouse model of TgCRND8 mice. Oncotarget 8(58):97900–97912

    Article  Google Scholar 

  28. 28.

    Yuan Q, Zhang H, Zhang X, Huang P, Liu R, Song YQ, Wu W, Lin ZX (2019) Association between axonopathy and amyloid plaques in the spinal cord of the transgenic mice of Alzheimer’s disease. Neuroscience 409:152–161

    CAS  Article  Google Scholar 

  29. 29.

    Omoto S, Ueno M, Mochio S, Yamashita T (2011) Corticospinal tract fibers cross the ephrin-B3-negative part of the midline of the spinal cord after brain injury. Neurosci Res 69(3):187–195

    CAS  Article  Google Scholar 

  30. 30.

    Durairajan SS, Liu LF, Lu JH, Chen LL, Yuan Q, Chung SK, Huang L, Li XS et al (2012) Berberine ameliorates beta-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model. Neurobiol Aging 33(12):2903–2919

    CAS  Article  Google Scholar 

  31. 31.

    Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S et al (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560(7717):185–191

    Article  Google Scholar 

  32. 32.

    Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J (2017) Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest 127(9):3210–3219

    Article  Google Scholar 

  33. 33.

    Ma Q, Ineichen BV, Detmar M, Proulx ST (2017) Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun 8(1):1434

    Article  Google Scholar 

  34. 34.

    Wang L, Zhang Y, Zhao Y, Marshall C, Wu T, Xiao M (2019) Deep cervical lymph node ligation aggravates AD-like pathology of APP/PS1 mice. Brain Pathol 29(2):176–192

    CAS  Article  Google Scholar 

  35. 35.

    Xu F, Kotarba AE, Ou-Yang MH, Fu Z, Davis J, Smith SO, Van Nostrand WE (2014) Early-onset formation of parenchymal plaque amyloid abrogates cerebral microvascular amyloid accumulation in transgenic mice. J Biol Chem 289(25):17895–17908

    CAS  Article  Google Scholar 

  36. 36.

    Hawkes CA, Gatherer M, Sharp MM, Dorr A, Yuen HM, Kalaria R, Weller RO, Carare RO (2013) Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-beta from the mouse brain. Aging Cell 12(2):224–236

    CAS  Article  Google Scholar 

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Acknowledgments

We would like to thank Yin Mei Wong for her technical assistance.

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Correspondence to Qiuju Yuan or Zhi-Xiu Lin.

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Supplementary Fig 1.
figure8

Characterization of Aβ pathology in the brain of aged TgCRND8 mice. A: The ratio of Aβ40/Aβ42 in the forebrain and CSF of aged TgCRND8 mice at the age of 18 months (n = 4). The level of Aβ40 of Aβ42 was measured by ELISA. Quantitative analysis revealed that ratio of Aβ40/Aβ42 was around 0.43, indicating the Aβ favors the formation for parenchymal plaques. The ratio of Aβ40/Aβ42 in CSF was much higher than that in the mouse forebrain. B and C: Aβ pathology in the brain revealed by Aβ (red) (B) and thioflavin S (green) (C) staining. Predominant parenchymal plaques were observed in the forebrain (thin arrows in B and C). In contrast, very limited CAA was seen in this region (thick arrow in B and C). D: Quantitative analysis for the mean area fraction of parenchymal plaques and CAA revealed parenchymal plaques are predominant Aβ pathology in the forebrain of TgCRND8 mice. * significantly different (p < 0.01) compared with the parenchymal plaques. Scale bar, 100 μm. (PNG 106 kb)

Supplementary Fig 2.
figure9

Blood vessel diameter in the ventral part is larger than that in the dorsal part of the spinal cord. Blood vessel diameters were measured in horizontal sections of cervical cord stained with lectin in the non-TgCRND8 mice at the age of 3 months (n = 5). The smallest distance across individual blood vessel was defined as the diameter of the blood vessel and was measured in NIH Image 1.6 software. Forty vessels in either the dorsal or ventral part of the spinal cord were measured in each animal. A: the dorsal part of the spinal cord. B: the ventral part of the spinal cord. Quantitative analysis revealed blood vessel diameter in the ventral part was significantly larger than that in the dorsal part. * significantly different (p < 0.001) compared with the dorsal part. Scale bar, 100 μm. (PNG 32 kb)

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Yuan, Q., Liu, X., Xian, YF. et al. Origins of Beta Amyloid Differ Between Vascular Amyloid Deposition and Parenchymal Amyloid Plaques in the Spinal Cord of a Mouse Model of Alzheimer’s Disease. Mol Neurobiol 57, 278–289 (2020). https://doi.org/10.1007/s12035-019-01697-4

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Keywords

  • β amyloid
  • Amyloid precursor protein
  • Alzheimer’s disease
  • Amyloid plaques
  • Cerebral amyloid angiopathy
  • Spinal cord