Advertisement

Activity-Induced Amyloid-β Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice

Published:November 02, 2018DOI:https://doi.org/10.1016/j.biopsych.2018.10.018

      Abstract

      Background

      A consistent proportion of individuals at risk for Alzheimer’s disease show intact cognition regardless of the extensive accumulation of amyloid-β (Aβ) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for Aβ can compensate for the underactivation of Aβ-positive ones to preserve cognition, but the underlying synaptic changes are still unexplored.

      Methods

      Using Golgi staining, we investigate how dendritic spines rearrange following contextual fear conditioning (CFC) in the hippocampus and amygdala of presymptomatic Tg2576 mice, a genetic model for Aβ accumulation. A molecular biology approach combined with intrahippocampal injection of a γ-secretase inhibitor evaluates the impact of Aβ fluctuations on spine rearrangements.

      Results

      Encoding of CFC increases Aβ oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of Aβ oligomers predicts vulnerability to network dysfunctions, as low c-Fos activation and spine maturation are detected in the hippocampus of Tg2576 mice upon recall of CFC memory. Rather, enhanced c-Fos activation and new spines are evident in the amygdala of Tg2576 mice compared with wild-type control mice. Preventing Aβ increase in the hippocampus of Tg2576 mice restores CFC-associated spine changes to wild-type levels in both the hippocampus and amygdala.

      Conclusions

      Our study provides the first evidence of neural compensation consisting of enhanced synaptic activity in brain regions spared by Aβ load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors Aβ oligomerization in the hippocampus and prevents synaptic rearrangements in this region.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bennett D.A.
        • Schneider J.A.
        • Arvanitakis Z.
        • Kelly J.F.
        • Aggarwal N.T.
        • Shah R.C.
        • Wilson R.S.
        Neuropathology of older persons without cognitive impairment from two community-based studies.
        Neurology. 2006; 66: 1837-18144
        • Aizenstein H.J.
        • Nebes R.D.
        • Saxton J.A.
        • Price J.C.
        • Mathis C.A.
        • Tsopelas N.D.
        • et al.
        Frequent amyloid deposition without significant cognitive impairment among the elderly.
        Arch Neurol. 2008; 65: 1509-1517
        • Morris J.C.
        • Roe C.M.
        • Xiong C.
        • Fagan A.M.
        • Goate A.M.
        • Holtzman D.M.
        • Mintun M.A.
        APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging.
        Ann Neurol. 2010; 67: 122-131
        • Sperling R.
        Potential of functional MRI as a biomarker in early Alzheimer's disease.
        Neurobiol Aging. 2011; 32: S37-S43
        • Bateman R.J.
        • Xiong C.
        • Benzinger T.L.
        • Fagan A.M.
        • Goate A.
        • Fox N.C.
        • et al.
        Dominantly inherited Alzheimer network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
        N Engl J Med. 2012; 30: 795-804
        • Fleisher A.S.
        • Chen K.
        • Quiroz Y.T.
        • Jakimovich L.J.
        • Gomez M.G.
        • Langois C.M.
        • et al.
        Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: A cross-sectional study.
        Lancet Neurol. 2012; 11: 1057-1065
        • Villemagne V.L.
        • Burnham S.
        • Bourgeat P.
        • Brown B.
        • Ellis K.A.
        • Salvado O.
        • et al.
        Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: A prospective cohort study.
        Lancet Neurol. 2013; 12: 357-367
        • Filippini N.
        • MacIntosh B.J.
        • Hough M.G.
        • Goodwin G.M.
        • Frisoni G.B.
        • Smith S.M.
        • et al.
        Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele.
        Proc Natl Acad Sci U S A. 2009; 28: 7209-7214
        • Elman J.A.
        • Oh H.
        • Madison C.M.
        • Baker S.L.
        • Vogel J.W.
        • Marks S.M.
        • et al.
        Neural compensation in older people with brain amyloid-β deposition.
        Nat Neurosci. 2014; 17: 1316-1318
        • Stern Y.
        Cognitive reserve.
        Neuropsychologia. 2009; 47: 2015-2028
        • Barulli D.
        • Stern Y.
        Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve.
        Trends Cogn Sci. 2013; 17: 502-509
        • Mondadori C.R.
        • Buchmann A.
        • Mustovic H.
        • Schmidt C.F.
        • Boesiger P.
        • Nitsch R.M.
        • et al.
        Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years.
        Brain. 2006; 129: 2908-2922
        • Terry D.
        • Sabatinelli D.
        • Puente A.N.
        • Lazar N.A.
        • Miller L.S.
        A meta-analysis of fMRI activation differences during episodic memory in Alzheimer's disease and mild cognitive impairment.
        J Neuroimaging. 2015; 25: 849-860
        • Palop J.J.
        • Mucke L.
        Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: From synapses toward neural networks.
        Nat Neurosci. 2010; 13: 812-818
        • Restivo L.
        • Vetere G.
        • Bontempi B.
        • Ammassari-Teule M.
        The formation of recent and remote memory is associated with time-dependent formation of dendritic spines in the hippocampus and anterior cingulate cortex.
        J Neurosci. 2009; 29: 8206-8214
        • Middei S.
        • Houeland G.
        • Cavallucci V.
        • Ammassari-Teule M.
        • D'Amelio M.
        • Marie H.
        CREB is necessary for synaptic maintenance and learning-induced changes of the AMPA receptor GluA1 subunit.
        Hippocampus. 2013; 23: 488-499
        • Pignataro A.
        • Middei S.
        • Borreca A.
        • Ammassari-Teule M.
        Indistinguishable pattern of amygdala and hippocampus rewiring following tone or contextual fear conditioning in C57BL/6 mice.
        Front Behav Neurosci. 2013; 7: 156
        • Maren S.
        • Phan K.L.
        • Liberzon I.
        The contextual brain: Implications for fear conditioning, extinction and psychopathology.
        Nat Rev Neurosci. 2013; 14: 417-428
        • LeDoux J.E.
        Emotion circuits in the brain.
        Annu. Rev. Neurosci. 2000; 23: 155-184
        • Lamprecht R.
        • LeDoux J.
        Structural plasticity and memory.
        Nat Rev Neurosci. 2004; 5: 45-54
        • Bero A.W.
        • Yan P.
        • Roh J.H.
        • Cirrito J.R.
        • Stewart F.R.
        • Raichle M.E.
        • et al.
        Neuronal activity regulates the regional vulnerability to amyloid-β deposition.
        Nat Neurosci. 2011; 14: 750-756
        • Shankar G.M.
        • Li S.
        • Mehta T.H.
        • Garcia-Munoz A.
        • Shepardson N.E.
        • Smith I.
        • et al.
        Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
        Nat Med. 2008; 14: 837-842
        • Selkoe D.J.
        • Hardy J.
        The amyloid hypothesis of Alzheimer's disease at 25 years.
        EMBO Mol Med. 2016; 8: 595-608
        • Zhao Y.
        • Sivaji S.
        • Chiang M.C.
        • Ali H.
        • Zukowski M.
        • Ali S.
        • et al.
        Amyloid beta peptides block new synapse assembly by nogo receptor-mediated inhibition of T-type calcium channels.
        Neuron. 2017; 11: 355-372.e6
        • Kamenetz F.
        • Tomita T.
        • Hsieh H.
        • Seabrook G.
        • Borchelt D.
        • Iwatsubo T.
        • et al.
        APP processing and synaptic function.
        Neuron. 2003; 37: 925-937
        • Cirrito J.R.
        • Yamada K.A.
        • Finn M.B.
        • Sloviter R.S.
        • Bales K.R.
        • May P.C.
        • et al.
        Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.
        Neuron. 2005; 48: 913-922
        • Hsiao K.
        • Chapman P.
        • Nilsen S.
        • Eckman C.
        • Harigaya Y.
        • Younkin S.
        • et al.
        Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.
        Science. 1996; 274: 99-102
        • D'Amelio M.
        • Cavallucci V.
        • Middei S.
        • Marchetti C.
        • Pacioni S.
        • Ferri A.
        • et al.
        Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease.
        Nat Neurosci. 2011; 14: 69-76
        • Meli G.
        • Lecci A.
        • Manca A.
        • Krako N.
        • Albertini V.
        • Benussi L.
        • et al.
        Conformational targeting of intracellular Aβ oligomers demonstrates theirpathological oligomerization inside the endoplasmic reticulum.
        Nat Commun. 2014; 5: 3867
        • Bezzina C.
        • Verret L.
        • Juan C.
        • Remaud J.
        • Halley H.
        • Rampon C.
        • Dahan L.
        Early onset of hypersynchronous network activity and expression of a marker of chronic seizures in the Tg2576 mouse model of Alzheimer's disease.
        PLoS One. 2015; 10: e0119910
        • Wheeler A.L.
        • Teixeira C.M.
        • Wang A.H.
        • Xiong X.
        • Kovacevic N.
        • Lerch J.P.
        • et al.
        Identification of a functional connectome for long-term fear memory in mice.
        PLoS Comput Biol. 2013; 9: e1002853
        • Portera-Cailliau C.
        Which comes first in fragile X syndrome, dendritic spine dysgenesis or defects in circuit plasticity.
        Neuroscientist. 2012; 18: 28-44
        • Oddi D.
        • Subashi E.
        • Middei S.
        • Bellocchio L.
        • Lemaire-Mayo V.
        • Guzmán M.
        • et al.
        Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome.
        Neuropsychopharmacology. 2015; 40: 1113-1122
        • Béïque J.C.
        • Andrade R.
        PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex.
        J Physiol. 2003; 546: 859-867
        • Kayed R.
        • Head E.
        • Sarsozam F.
        • Saingm T.
        • Cotman C.W.
        • Necula M.
        • et al.
        Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers.
        Mol Neurodegener. 2007; 2: 18
        • Kayed R.
        • Head E.
        • Thompson J.L.
        • McIntire T.M.
        • Milton S.C.
        • Cotman C.W.
        • Glabe C.G.
        Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
        Science. 2003; 300: 486-489
        • Huijbers W.
        • Mormino E.C.
        • Wigman S.E.
        • Ward A.M.
        • Vannini P.
        • McLaren D.G.
        • et al.
        Amyloid deposition is linked to aberrant entorhinal activity among cognitively normal older adults.
        J Neurosci. 2014; 34: 5200-5210
        • Stern Y.
        • Moeller J.R.
        • Anderson K.E.
        • Luber B.
        • Zubin N.R.
        • DiMauro A.A.
        • et al.
        Different brain networks mediate task performance in normal aging and AD: defining compensation.
        Neurology. 2000; 55: 1291-1297
        • Dickerson B.C.
        • Salat D.H.
        • Greve D.N.
        • Chua E.F.
        • Rand-Giovannetti E.
        • Rentz D.M.
        • et al.
        Increased hippocampal activation in mild cognitive impairment compared with normal aging and AD.
        Neurology. 2005; 65: 404-411
        • Liu P.
        • Reed M.N.
        • Kotilinek L.A.
        • Grant M.K.
        • Forster C.L.
        • Qiang W.
        • et al.
        Quaternary structure defines a large class of amyloid-β oligomers neutralized by sequestration.
        Cell Rep. 2015; 11: 1760-1771
        • Randall F.E.
        • Whittington M.A.
        • Cunningham M.O.
        Fast oscillatory activity induced by kainate receptor activation in the rat basolateral amygdala in vitro.
        Eur J Neurosci. 2011; 33: 914-922
        • Iaccarino H.F.
        • Singer A.C.
        • Martorell A.J.
        • Rudenko A.
        • Gao F.
        • Gillingham T.Z.
        • et al.
        Gamma frequency entrainment attenuates amyloid load and modifies microglia.
        Nature. 2016; 540: 230-235
        • Maesako M.
        • Uemura K.
        • Kubota M.
        • Kuzuya A.
        • Sasaki K.
        • Hayashida N.
        • et al.
        Exercise is more effective than diet control in preventing high fat diet-induced β-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice.
        J Biol Chem. 2012; 287: 23024-23033
        • Verret L.
        • Krezymon A.
        • Halley H.
        • Trouche S.
        • Zerwas M.
        • Lazouret M.
        • et al.
        Transient enriched housing before amyloidosis onset sustains cognitive improvement in Tg2576 mice.
        Neurobiol Aging. 2013; 34: 211-225
        • Rodríguez J.J.
        • Noristani H.N.
        • Verkhratsky A.
        Microglial response to Alzheimer's disease is differentially modulated by voluntary wheel running and enriched environments.
        Brain Struct Funct. 2015; 220: 941-953
        • Verghese J.
        • Lipton R.B.
        • Katz M.J.
        • Hall C.B.
        • Derby C.A.
        • Kuslansky G.
        • et al.
        Leisure activities and the risk of dementia in the elderly.
        N Engl J Med. 2003; 348: 2508-2516
        • Andel R.
        • Vigen C.
        • Mack W.J.
        • Clark L.J.
        • Gatz M.
        The effect of education and occupational complexity on rate of cognitive decline in Alzheimer's patients.
        J Int Neuropsychol Soc. 2006; 12: 147-152
        • Mistridis P.
        • Mata J.
        • Neuner-Jehle S.
        • Annoni J.M.
        • Biedermann A.
        • Bopp-Kistler I.
        • et al.
        Use it or lose it! Cognitive activity as a protective factor for cognitive decline associated with Alzheimer's disease.
        Swiss Med Wkly. 2017; 147: w14407
        • Buckner R.L.
        • Snyder A.Z.
        • Shannon B.J.
        • LaRossa G.
        • Sachs R.
        • Fotenos A.F.
        • et al.
        Molecular, structural, and functional characterization of Alzheimer's disease: Evidence for a relationship between default activity, amyloid, and memory.
        J Neurosci. 2005; 25: 7709-7717
        • Oh H.
        • Razlighi Q.R.
        • Stern Y.
        Multiple pathways of reserve simultaneously present in cognitively normal older adults.
        Neurology. 2018; 90: e197-e205
        • Qureshi S.U.
        • Kimbrell T.
        • Pyne J.M.
        • Magruder K.M.
        • Hudson T.J.
        • Petersen N.J.
        • et al.
        Greater prevalence and incidence of dementia in older veterans with posttraumatic stress disorder.
        J Am Geriatr Soc. 2010; 58: 1627-1633
        • Yaffe K.
        • Vittinghoff E.
        • Lindquist K.
        • Barnes D.
        • Covinsky K.E.
        • Neylan T.
        • et al.
        Posttraumatic stress disorder and risk of dementia among US veterans.
        Arch Gen Psychiatry. 2010; 67: 608-613
        • Maya Y.
        • Okumura Y.
        • Kobayashi R.
        • Onishi T.
        • Shoyama Y.
        • Barret O.
        • et al.
        Preclinical properties and human in vivo assessment of 123I-ABC577 as a novel SPECT agent for imaging amyloid-β.
        Brain. 2016; 139: 193-203
        • Sevigny J.
        • Chiao P.
        • Bussière T.
        • Weinreb P.H.
        • Williams L.
        • Maier M.
        • et al.
        The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.
        Nature. 2016; 537: 50-56
        • Van Dyck C.H.
        Anti-amyloid-β monoclonal antibodies for Alzheimer's disease: Pitfalls and promise.
        Biol Psychiatry. 2018; 83: 311-319

      Linked Article

      • Amyloid-β–Dependent Neuronal Circuit Rearrangement in Presymptomatic Alzheimer’s Disease
        Biological PsychiatryVol. 86Issue 3
        • Preview
          With the advances of modern medicine, people are living longer than ever before worldwide. Consequently, an increase in patients with dementia has become a serious social concern, with Alzheimer’s disease (AD) being the most common form of dementia. In 2015, the World Alzheimer Report estimated that approximately 46.8 million people had AD and other types of dementia worldwide. Accordingly, the number of such patients is predicted to increase to more than 131.5 million by the year 2050. Therefore, the development of new therapeutic alternatives to control AD progression and even reverse the disease is urgently needed.
        • Full-Text
        • PDF