10 Jul 2015

When given blood from old mice, young mice age quickly, implying that some factor lurks in the circulatory milieu to speed the aging process (see May 2014 news story). In the July 6 Nature Medicine, scientists led by Saul Villeda, University of California, San Francisco, identify one potential candidate, a protein called β2-microglobulin (B2M). Older mice had more B2M in their blood, while injecting it into the brain or bloodstream of young mice impaired memory and suppressed neurogenesis, the authors report. Genetically knocking down B2M had the opposite effect. “This is an elegant paper,” said Henrik Zetterberg, University of Gothenburg, Sweden, who was not involved in the research. “It suggests reducing levels of β2-microglobulin could be good from a treatment perspective.”

Dorothy Schafer, University of Massachusetts Medical School, Worcester, agreed. “An important next step is to understand the role of this molecular pathway in models of neurodegenerative disease,” she wrote to Alzforum.

B2M forms part of the major histocompatibility complex class I (MHC I), which sits on the surface of immune cells and displays antigens to cytotoxic T cells. In a completely separate capacity, B2M and MHC I also help regulate normal brain development, synaptic plasticity, and behavior (for a review, see Boulanger & Schatz, 2004).

In previous work, Villeda and colleagues led by Tony Wyss-Coray, Stanford University School of Medicine, California, found B2M among a select few proteins that are elevated in aged mice and correlate with poor neurogenesis in the brain. These proteins also compromised neurogenesis in young mice that share the blood of older animals in a circulatory ménage called parabiosis (Aug 2011 news story).

Now running his own lab, Villeda decided to look at B2M more closely because it has been reported to tick up in the blood of HIV patients with dementia, in people who become cognitively impaired while undergoing chronic dialysis, and perhaps even in the cerebrospinal fluid (CSF) of patients with Alzheimer’s or Parkinson’s disease (Corlin et al., 2005; Murray, 2008; Brew et al., 1996; Carrette et al., 2003, Zhang et al., 2008).

Villeda wondered whether B2M is a cause or consequence of aging. At the outset, co-first authors Lucas Smith, Gregor Bieri, and Cedric Snethlage of UCSF, and Yingbo He and Jeong-Soo Park at Stanford, confirmed the age-related increase of plasma B2M. Two-year-old mice had about four times the amount of three-month-olds. Similarly, the researchers found more B2M in archived CSF from healthy older people aged 60 to 95 compared to those 20 to 45. Though more variable, blood also reflected this age-related rise in B2M.

Next, to see if the globulin increases affected hippocampal-dependent learning and memory, the researchers injected the human protein into either the bloodstream or the hippocampus of young mice to double the amount of protein normally found in aged animals. Treated mice froze less in a contextual memory task and made more mistakes in the radial arm water maze than controls. Researchers testing the animals were blinded to the treatment. Neurogenesis nudged down by about 20 percent (see image above). Interestingly, memory deficits faded 30 days after injection, which was when normal neurogenesis resumed, Villeda told Alzforum. This suggests that impairments caused by B2M are reversible and related to reductions in the complement of new neurons, Villeda said. Both the cognitive problems and the drop in neurogenesis appeared to require MHC I, because young mice lacking the protein that transports MHC I to the cell surface showed no ill effects of injected B2M.

Mice without B2M performed better in memory tests. Compared to age-matched controls, 17-month-old B2M knockout mice committed half as many errors on the radial arm water maze and froze nearly twice as often in a contextual fear setting. Neurogenesis surpassed wild-type levels. The data peg B2M as one factor that accelerates brain aging in mice, the authors believe.

“Together, the results suggest suppressing B2M in old age could benefit cognition,” Villeda told Alzforum. He proposed different ways of doing that, such as neutralizing the protein with an antibody, interfering with its MHC I interaction, or even removing B2M from blood using some form of dialysis.

Villeda does not yet know whether B2M causes aging because of its immune functions, effects on the brain, or both. He intends to correlate B2M levels in older people with cognitive deficits.  

B2M is not the only aging factor in the blood, said Villeda. While in Wyss-Coray's lab he found that the chemokine eotaxin also drives aging and since then a genetics study has implicated this protein in age of onset of Alzheimer’s disease (Nov 2009 conference news, Apr 2015 conference news). So far, no manipulation of any one factor seems to accelerate aging in mice as much as hooking their circulatory system up to that of an older animal, he noted.

Zetterberg commented that he has seen elevated B2M levels in CSF from people with parkinsonian disorders (Constantinescu et al., 2010). CSF B2M elevations could result from a leaky blood-brain barrier or elevated production by activated microglia, he speculated. He sees potential for B2M to serve as a biomarker of general neurodegenerative diseases.

The findings also fit with work from Carla Schatz, at Stanford. She previously reported that synaptic networks in hippocampi and visual cortices of B2M knockouts are more plastic than those in controls (Huh et al., 2000; Datwani et al., 2009). "It could be that the loss of B2M leads to enhanced plasticity, whereas excessive B2M dampens it," she said.—Gwyneth Dickey Zakaib

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References

News Citations

1. In Revival of Parabiosis, Young Blood Rejuvenates Aging Microglia, Cognition 5 May 2014
2. Paper Alert: Do Blood-Borne Factors Control Brain Aging? 31 Aug 2011
3. Chicago: The Vampire Principle—Young Blood Rejuvenates Aging Brain? 20 Nov 2009
4. New Genetics Frontiers: Finding Modifiers, Making Sense of Pathways 10 Apr 2015

Paper Citations

1. Boulanger LM, Shatz CJ. Immune signalling in neural development, synaptic plasticity and disease. Nat Rev Neurosci. 2004 Jul;5(7):521-31. PubMed.
3. Murray AM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Adv Chronic Kidney Dis. 2008 Apr;15(2):123-32. PubMed.
4. Brew BJ, Dunbar N, Pemberton L, Kaldor J. Predictive markers of AIDS dementia complex: CD4 cell count and cerebrospinal fluid concentrations of beta 2-microglobulin and neopterin. J Infect Dis. 1996 Aug;174(2):294-8. PubMed.
5. Carrette O, Demalte I, Scherl A, Yalkinoglu O, Corthals G, Burkhard P, Hochstrasser DF, Sanchez JC. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease. Proteomics. 2003 Aug;3(8):1486-94. PubMed.
6. Zhang J, Sokal I, Peskind ER, Quinn JF, Jankovic J, Kenney C, Chung KA, Millard SP, Nutt JG, Montine TJ. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol. 2008 Apr;129(4):526-9. PubMed.
7. Constantinescu R, Andreasson U, Li S, Podust VN, Mattsson N, Anckarsäter R, Anckarsäter H, Rosengren L, Holmberg B, Blennow K, Wikkelsö C, Rüetschi U, Zetterberg H. Proteomic profiling of cerebrospinal fluid in parkinsonian disorders. Parkinsonism Relat Disord. 2010 Sep;16(8):545-9. PubMed.
8. Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ. Functional requirement for class I MHC in CNS development and plasticity. Science. 2000 Dec 15;290(5499):2155-9. PubMed.
9. Datwani A, McConnell MJ, Kanold PO, Micheva KD, Busse B, Shamloo M, Smith SJ, Shatz CJ. Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity. Neuron. 2009 Nov 25;64(4):463-70. PubMed.

Further Reading

Papers

1. Bouchard J, Villeda SA. Aging and brain rejuvenation as systemic events. J Neurochem. 2015 Jan;132(1):5-19. Epub 2014 Dec 5 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.

News

1. New Genetics Frontiers: Finding Modifiers, Making Sense of Pathways 10 Apr 2015
2. Blessing or Curse? Peripheral Cytokines in the Brain 22 Mar 2013
3. X-raying Aβ Oligomers, Unraveling Mysteries of Amyloid Aggregation 2 Feb 2011
4. In Aging Brain, Blood-Brain Barrier Starts Leaking in Hippocampus 30 Jan 2015