Bu, Kivipelto, Cirrito, and Slutsky Win MetLife Awards

For the 30th year in a row, the MetLife Foundation has awarded major prizes for the study of Alzheimer’s disease. Four scientists were bestowed with the honor this year. Guojun Bu of the Mayo Clinic in Jacksonville, Florida, and Miia Kivipelto of the Karolinska Institute in Stockholm received major awards, while John Cirrito, Washington University in St. Louis, and Inna Slutsky, Tel Aviv University in Israel, won promising investigator awards.

Bu was awarded for his pioneering work on lipoprotein-related protein 1 (LRP1), a lipoprotein receptor. His early research helped uncover a connection between LRP1 and ApoE, a major risk factor for AD (see Holtzman et al., 1995). In 2007, his lab discovered that amyloid precursor protein (APP) suppresses the expression of LRP1, which promotes uptake of ApoE, thus linking genetic determinants of early and late-onset AD (see Oct 2007 news on Liu et al., 2007). Bu’s group later reported that mice lacking LRP1 in neurons had problems with lipid metabolism as well as synapse loss and neurodegeneration (see Liu et al., 2010, and Jul 2010 conference news). His lab found that the receptor facilitated the uptake of Aβ into neurons (see Fuentealba et al., 2010), and along with collaborators from David Holtzman’s lab at WashU, Bu later reported that ApoE competes with Aβ for binding to LRP1, thus preventing the clearance of Aβ by astrocytes (see Apr 2013 news). He recently reported that ApoE latches onto cell surface heparin sulfate proteoglycans (HSPGs), preventing their uptake of Aβ, and onto TREM2, a microglial cell surface receptor implicated in Aβ clearance (see Apr 2016 news and Atagi et al., 2015). 

Kivipelto’s scientific career is firmly rooted in the idea that healthy living in mid-life may prevent or slow the onslaught of dementia later on. Starting at the turn of the century, she linked poor mid-life cardiovascular health to AD and mild cognitive impairment (see Kivipelto et al., 2001; Kivipelto et al., 2001). Kivipelto went on to weave in other genetic and lifestyle factors—such as ApoE4, diet, smoking, and exercise (see Kivipelto et al., 2002; Rovio et al., 2005; Laitinen et al., 2006; and Aug 2006 news). Because much of her data pointed to connections between lifestyle and dementia, Kivipelto moved into intervention mode with the ongoing FINGER trial—in which participants at risk for cognitive decline take on healthy changes in exercise, diet, and cognitive and social stimulation (see clinicaltrials.gov and Kivipelto et al., 2013). The study has not determined  whether the interventions will stop or slow the onset of dementia, however, participants in the intervention groups have reaped cognitive rewards (see Jul 2014 conference news and Nov 2015 conference news). 

As a graduate student in David Holtzman’s lab at WashU, Cirrito developed a brain microdialysis technique to monitor Aβ in the interstitial fluid of freely moving mice (see Oct 2003 news on Cirrito et al., 2003). This intensive monitoring revealed that Aβ in plaques existed in dynamic equilibrium with a pool of soluble Aβ. Cirrito later used the technique to reveal that synaptic activity drives Aβ release from neurons (see Dec 2005 conference news and Cirrito et al., 2005). From the helm of his own lab at WashU, Cirrito developed an Aβ electrode that could monitor Aβ on the order of seconds, rather than minutes, an improvement that helped reveal that Aβ clearance from the interstitial fluid follows biphasic kinetics (see Nov 2014 news and Yuede et al., 2016). His lab has also reported that the anti-depressant citalopram decreases CSF concentration of Aβ in people and reduces plaques in AD model mice (see May 2014 news). 

As an electrophysiologist, Slutsky focuses on the relationship between synaptic transmission and Aβ. In 2009, Slutsky reported that short-term synaptic plasticity was thrown out of whack when Aβ was either low or high (see Nov 2009 news). She later reported that neuronal spike bursts increased the ratio of Aβ40 to Aβ42 by altering the conformation of presenilin 1 (see Dolev et al., 2013). Her work has also uncovered how local fluctuations in GABA concentrations can modulate transmission of hippocampal neurons, which are acutely affected during Alzheimer’s disease (see Laviv et al., 2010; Slomowitz et al., 2015; and Gazit et al., 2016). 

The researchers were presented with their awards at Alzheimer’s Association International Conference in Toronto today. Major awards received by Bu and Kivipelto included a $100,000 institutional grant and $25,000 personal grant, while Cirrito and Slutsky received $50,000 institutional grants.—Jessica Shugart

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References

News Citations

  1. APP—Making Heads and Tails of the ApoE, Cholesterol Connection
  2. St. Louis: ApoE—Receptors, Theories and Therapies
  3. ApoE Does Not Bind Aβ, Competes for Clearance
  4. Sticky Matrix Proteins Lead to Amyloid Accumulation, Slow Clearance
  5. Crystal Ball for AD? Studies Quantitate Risk Factors, Markers of Progression
  6. Healthy Lives, Healthy Minds: Is it Really True?
  7. Health Interventions Boost Cognition—But Do They Delay Dementia?
  8. Soluble Aβ: Getting a Grip on Its Fate
  9. SfN: Where, How Does Intraneuronal Aβ Pack Its Punch? Part 2
  10. Measuring Rapid Changes in Brain Aβ in Live Mice
  11. Antidepressant Citalopram Shows Promise as Future Anti-Amyloid Agent
  12. What’s My Line?—Fishing for the True Role of Aβ

Paper Citations

  1. Holtzman DM, Pitas RE, Kilbridge J, Nathan B, Mahley RW, Bu G, Schwartz AL. Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9480-4. PubMed.
  2. Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, Bu G. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron. 2007 Oct 4;56(1):66-78. PubMed.
  3. Liu Q, Trotter J, Zhang J, Peters MM, Cheng H, Bao J, Han X, Weeber EJ, Bu G. Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. J Neurosci. 2010 Dec 15;30(50):17068-78. PubMed.
  4. Fuentealba RA, Liu Q, Zhang J, Kanekiyo T, Hu X, Lee JM, LaDu MJ, Bu G. Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking. PLoS One. 2010;5(7):e11884. PubMed.
  5. Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, Li X, Rademakers R, Kang SS, Xu H, Younkin S, Das P, Fryer JD, Bu G. Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). J Biol Chem. 2015 Oct 23;290(43):26043-50. Epub 2015 Sep 15 PubMed.
  6. Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ. 2001 Jun 16;322(7300):1447-51. PubMed.
  7. Kivipelto M, Helkala EL, Hänninen T, Laakso MP, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study. Neurology. 2001 Jun 26;56(12):1683-9. PubMed.
  8. Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002 Aug 6;137(3):149-55. PubMed.
  9. Rovio S, Kåreholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol. 2005 Nov;4(11):705-11. PubMed.
  10. Laitinen MH, Ngandu T, Rovio S, Helkala EL, Uusitalo U, Viitanen M, Nissinen A, Tuomilehto J, Soininen H, Kivipelto M. Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study. Dement Geriatr Cogn Disord. 2006;22(1):99-107. PubMed.
  11. Kivipelto M, Solomon A, Ahtiluoto S, Ngandu T, Lehtisalo J, Antikainen R, Bäckman L, Hänninen T, Jula A, Laatikainen T, Lindström J, Mangialasche F, Nissinen A, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): Study design and progress. Alzheimers Dement. 2013 Jan 16; PubMed.
  12. Cirrito JR, May PC, O'Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, Demattos RB, Holtzman DM. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci. 2003 Oct 1;23(26):8844-53. PubMed.
  13. Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. PubMed.
  14. Yuede CM, Lee H, Restivo JL, Davis TA, Hettinger JC, Wallace CE, Young KL, Hayne MR, Bu G, Li CZ, Cirrito JR. Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model. J Exp Med. 2016 May 2;213(5):677-85. Epub 2016 Apr 11 PubMed.
  15. Dolev I, Fogel H, Milshtein H, Berdichevsky Y, Lipstein N, Brose N, Gazit N, Slutsky I. Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change. Nat Neurosci. 2013 May;16(5):587-95. PubMed.
  16. Laviv T, Riven I, Dolev I, Vertkin I, Balana B, Slesinger PA, Slutsky I. Basal GABA regulates GABA(B)R conformation and release probability at single hippocampal synapses. Neuron. 2010 Jul 29;67(2):253-67. PubMed.
  17. Slomowitz E, Styr B, Vertkin I, Milshtein-Parush H, Nelken I, Slutsky M, Slutsky I. Interplay between population firing stability and single neuron dynamics in hippocampal networks. Elife. 2015 Jan 3;4 PubMed.
  18. Gazit N, Vertkin I, Shapira I, Helm M, Slomowitz E, Sheiba M, Mor Y, Rizzoli S, Slutsky I. IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses. Neuron. 2016 Feb 3;89(3):583-97. Epub 2016 Jan 21 PubMed.

External Citations

  1. clinicaltrials.gov

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