Young Blood a Boon for APP Mice

Splicing the circulatory system of a young mouse into that of an older one bolsters the aged brain. Might the same treatment work in mouse models of Alzheimer’s disease? A new study, from the lab of Tony Wyss-Coray at Stanford School of Medicine in California, suggests it does. The researchers found that the blood-sharing strategy, known as parabiosis, normalized the expression of synaptic and neuronal proteins in mice expressing a mutant human APP transgene. Injecting plasma from young wild-type animals into these same models improved memory. However, neither treatment reduced plaque load. The results hint that something circulating in the blood helps neurons and synapses compensate for the effects of Aβ pathology.

“It seems as though factors in young blood—probably proteins—have positive effects on brains that are degenerated from Alzheimer’s-like disease,” said first author Jinte Middeldorp, who has since moved to the University Medical Center Utrecht in the ‎Netherlands.

Synapses Restored: Synaptophysin (red) marks presynaptic terminals, which fade away in the dentate gyrus of aged APP mice (middle), but not if they share blood with normal young mice (right). [©2016 American Medical Association. All rights reserved.]

Scientists in Wyss-Coray’s lab and others previously reported that parabiosis with young animals improved synaptic plasticity, normalized the expression of learning and memory genes in the hippocampus, and improved vascular function in aging wild-type mice (Villeda et al., 2014; Katsimpardi et al., 2014). To see if this treatment could similarly help mouse models of early AD, Middeldorp and colleagues surgically connected young wild-type mice to 16- to 20-month-old male and 10- to 12-month-old female APP mice. These animals express APP with both Swedish and London mutations, which increase Aβ production and boost the Aβ42:Aβ40 ratio, respectively. At these advanced ages, the mice have accumulated plaques, lost synapses, and perform poorly in tests of learning and memory.  

After five weeks of parabiosis, young mouse blood appeared to have no effect on either Aβ immunoreactivity or microglial activation in the APP mice. However, the AD mice had wild-type levels of both the synapse protein synaptophysin (see image above) and the calcium-binding protein calbindin in their hippocampi. By contrast, those proteins waned in control parabiotic APP-APP mouse pairs. Given that synaptophysin and calbindin fall in female APP mice by nine months of age (Pickford et al., 2008), Middeldorp believes that young plasma reversed that decline. Taken together, the data suggest synapses are healthier when APP mice have some young blood coursing through their veins. Interestingly, levels of synaptophysin and calbindin reportedly decline in the brains of patients with AD (Masliah et al., 2001; Palop et al., 2003). 

To look for a possible mechanism for these protein changes, Middeldorp and colleagues screened for genes that were differentially regulated in the young-old pairs compared to the isochronic APP-APP conjoined mice. NFkB and p38 MAPK, two proteins that regulate extracellular receptor kinase (ERK) kinase signaling, and some calcium-ion binding genes changed most, with expression shifting toward wild-type levels. The findings suggest that some factors in young blood protect synapses at least in part by normalizing neuronal signaling pathways. Previous studies have reported that ERK becomes hyperphosphorylated and overactive in AD (Webster et al., 2006). 

Would these protein and gene changes translate to cognitive benefits? Because it is impossible to test conjoined animals in typical learning and memory tasks, which were designed for individual, freely running mice, the researchers used a different approach to answer this question. They injected plasma from young, wild-type mice into 10- to 12-month-old female APP mice twice a week for four weeks. Wyss-Coray had previously found this yielded comparable outcomes to parabiosis. A control group of APP mice got saline injections. Mice receiving the plasma better remembered which arms they had explored in a Y-maze test and froze more in a contextual fear-conditioning task. At the same time, phosphorylation of ERK, as well as levels of synaptophysin and calbindin, matched wild-type levels.

Which blood factors modify neurons? Hints come from proteomic analysis. Wyss-Coray previously reported that elevated eotaxin, a chemokine, suppressed neurogenesis in aging mice, while others proposed that the immune-related protein β2-microglobulin did the same and weakened memory (Aug 2011 news; Jul 2015 news). Wyss-Coray and colleagues are also working to identify protective molecules in young blood. Multiple factors may contribute to the effects, the authors wrote.

Marco Colonna, Washington University School of Medicine, St. Louis, who was not involved with the study, was surprised that a synaptic benefit surfaced with no change in Aβ plaque load or microglial activation. “The amelioration seems to be due to plasma’s direct effects on neurons and synapses,” he said. He suggested that plasma helps the neurons tolerate stress brought on by the accumulation of Aβ, but he wondered if longer treatment with young blood might eventually reduce Aβ levels. He added that it would be interesting to extend these experiments to models of other neurodegenerative diseases to see if plasma benefits neurons more generally.

Could these observations lead to an Alzheimer’s treatment? Intravenous administration of plasma is approved as a therapy to replace blood-clotting factors in surgery, in bleeding emergencies, and routinely in people who lack certain clotting factors from birth. For AD, Sharon Sha and colleagues, also at Stanford University, are collaborating with the San Carlos, California-based company Alkahest in the ongoing PLasma for Alzheimer SymptoM Amelioration Study (PLASMA), which tests whether once-weekly treatment with plasma is safe and effective in 18 patients with mild to moderate AD. Sha wrote to Alzforum that the trial is in the final stages of enrollment. Alkahest gets support from Grifols, a transfusion, blood banking, and protein therapeutics company based in Barcelona.—Gwyneth Dickey Zakaib

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References

News Citations

  1. Paper Alert: Do Blood-Borne Factors Control Brain Aging?
  2. β2-Microglobulin: A Blood-Borne Aging Factor?

Therapeutics Citations

  1. Young Plasma

Paper Citations

  1. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014 Jun;20(6):659-63. Epub 2014 May 4 PubMed.
  2. Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014 May 9;344(6184):630-4. Epub 2014 May 5 PubMed.
  3. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008 Jun;118(6):2190-9. PubMed.
  4. Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW, Morris JC. Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease. Neurology. 2001 Jan 9;56(1):127-9. PubMed.
  5. Palop JJ, Jones B, Kekonius L, Chin J, Yu GQ, Raber J, Masliah E, Mucke L. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9572-7. Epub 2003 Jul 24 PubMed.
  6. Webster B, Hansen L, Adame A, Crews L, Torrance M, Thal L, Masliah E. Astroglial activation of extracellular-regulated kinase in early stages of Alzheimer disease. J Neuropathol Exp Neurol. 2006 Feb;65(2):142-51. PubMed.

Other Citations

  1. APP mice

Further Reading

Papers

  1. Castellano JM, Palner M, Li SB, Freeman GM Jr, Nguyen A, Shen B, Stan T, Mosher KI, Chin FT, de Lecea L, Luo J, Wyss-Coray T. In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model. Sci Rep. 2016 Jul 1;6:29015. PubMed.
  2. Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016 May 2;213(5):667-75. Epub 2016 Apr 18 PubMed.
  3. Xiang Y, Bu XL, Liu YH, Zhu C, Shen LL, Jiao SS, Zhu XY, Giunta B, Tan J, Song WH, Zhou HD, Zhou XF, Wang YJ. Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer's disease. Acta Neuropathol. 2015 Oct;130(4):487-99. Epub 2015 Sep 12 PubMed.

Primary Papers

  1. Middeldorp J, Lehallier B, Villeda SA, Miedema SS, Evans E, Czirr E, Zhang H, Luo J, Stan T, Mosher KI, Masliah E, Wyss-Coray T. Preclinical Assessment of Young Blood Plasma for Alzheimer Disease. JAMA Neurol. 2016 Nov 1;73(11):1325-1333. PubMed.

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