Multiple events lead to dendritic spine loss in triple transgenic Alzheimer’s disease mice
Open accessAbstract
The pathology of Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptide, hyperphosphorylated tau protein, neuronal death, and synaptic loss. By means of long-term two-photon in vivo imaging and confocal imaging, we characterized the spatio-temporal pattern of dendritic spine loss for the first time in 3xTg-AD mice. These mice exhibit an early loss of layer III neurons at 4 months of age, at a time when only soluble Aβ is abundant. Later on, dendritic spines are lost around amyloid plaques once they appear at 13 months of age. At the same age, we observed spine loss also in areas apart from amyloid plaques. This plaque independent spine loss manifests exclusively at dystrophic dendrites that accumulate both soluble Aβ and hyperphosphorylated tau intracellularly. Collectively, our data shows that three spatio-temporally independent events contribute to a net loss of dendritic spines. These events coincided either with the occurrence of intracellular soluble or extracellular fibrillar Aβ alone, or the combination of intracellular soluble Aβ and hyperphosphorylated tau.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The 3xTg-AD mouse has cognitive decline particularly in long term memory.
“intraneuronal Aβ accumulation and cognitive decline particularly in long term memory (Bittner et al., 2010).”
From Early stage alterations in white matter and decreased functional interhemispheric hippocampal connectivity in the 3xTg mouse model of Alzheimer’s disease. (2019) · cites this paper as Bittner et al., 2010
The Discussion (page unavailable) says that 3xTg-AD mice show cognitive decline as early as 4–6 months and describes intracellular accumulation of oligomeric Aβ. It does not specify that the decline is particularly in long-term memory. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExpression of mutant tau in mouse models of Alzheimer's disease-like tau neuropathologies can result in a significant loss of dendritic spines and synapses.
“Significantly, the expression of mutant tau in mouse models of Alzheimer’s disease-like tau neuropathologies can result in a significant loss of dendritic spines and synapses (Mocanu et al., 2008; Bittner et al., 2010; Rocher et al., 2010).”
From The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease (2013) · cites this paper as Bittner et al., 2010
The Results identify a mutant tau transgene (tauP301L) in the 3xTg-AD mice and report significantly reduced dendritic spine density; the Introduction treats spines as indicators of excitatory synapses. But the Discussion associates spine loss with Aβ alone or with Aβ and hyperphosphorylated tau together. The paper does not establish that expression of mutant tau itself caused the loss. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe 3xTg-AD mouse has intraneuronal Aβ accumulation.
“intraneuronal Aβ accumulation and cognitive decline particularly in long term memory (Bittner et al., 2010).”
From Early stage alterations in white matter and decreased functional interhemispheric hippocampal connectivity in the 3xTg mouse model of Alzheimer’s disease. (2019) · cites this paper as Bittner et al., 2010
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 54 · Cited by 149
Research works printed but not linked: 38
- [1]Terry RD Masliah E Salmon DP Butters N DeTeresa R 1991 Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30 572 580 1789684
- [2]Selkoe DJ 2002 Alzheimer's disease is a synaptic failure. Science 298 789 791 12399581
- [3]Davies CA Mann DMA Sumpter PQ Yates PO 1987 A Quantitative Morphometric Analysis of the Neuronal and Synaptic Content of the Frontal and Temporal Cortex in Patients with Alzheimers-Disease. Journal of the Neurological Sciences 78 151 164 3572454
- [4]Masliah E Terry RD Deteresa RM Hansen LA 1989 Immunohistochemical Quantification of the Synapse-Related Protein Synaptophysin in Alzheimer-Disease. Neurosci Lett 103 234 239 2505201
- [5]DeKosky ST Scheff SW 1990 Synapse Loss in Frontal-Cortex Biopsies in Alzheimers-Disease - Correlation with Cognitive Severity. Ann Neurol 27 457 464 2360787
- [6]Dickson DW Crystal HA Bevona C Honer W Vincent I 1995 Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16 285 298 7566338
- [8]Scheff SW Price DA Schmitt FA Mufson EJ 2006 Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 27 1372 1384 16289476
- [9]Akram A Christoffel D Rocher AB Bouras C Kovari E 2008 Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease. Neurobiol Aging 29 1296 1307 17420070 PMC2569870
- [12]Lue LF Kuo YM Roher AE Brachova L Shen Y 1999 Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 155 853 862 10487842 PMC1866907
- [14]Blennow K Bogdanovic N Alafuzoff I Ekman R Davidsson P 1996 Synaptic pathology in Alzheimer's disease: Relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. Journal of Neural Transmission 103 603 618 8811505
- [16]Lanz TA Carter DB Merchant KM 2003 Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol Dis 13 246 253 12901839
- [17]Jacobsen JS Wu CC Redwine JM Comery TA Arias R 2006 Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 103 5161 5166 16549764 PMC1405622
- [18]Mucke L Masliah E Yu GQ Mallory M Rockenstein EM 2000 High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20 4050 4058 10818140 PMC6772621
- [19]Moechars D Dewachter I Lorent K Reverse D Baekelandt V 1999 Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274 6483 6492 10037741
- [20]Holcomb L Gordon MN McGowan E Yu X Benkovic S 1998 Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4 97 100 9427614
- [22]Hsieh H Boehm J Sato C Iwatsubo T Tomita T 2006 AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52 831 843 17145504 PMC1850952
- [24]Shankar GM Li SM Mehta TH Garcia-Munoz A Shepardson NE 2008 Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Medicine 14 837 842 PMC2772133 18568035
- [25]Wei W Nguyen LN Kessels HW Hagiwara H Sisodia S 2010 Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nature Neuroscience 13 190 U71 20037574 PMC3310198
- [26]Tsai J Grutzendler J Duff K Gan WB 2004 Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7 1181 1183 15475950
- [28]Koffie RM Meyer-Luehmann M Hashimoto T Adams KW Mielke ML 2009 Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proceedings of the National Academy of Sciences of the United States of America 106 4012 4017 19228947 PMC2656196
- [29]Knafo S Alonso-Nanclares L Gonzalez-Soriano J Merino-Serrais P Fernaud-Espinosa I 2009 Widespread Changes in Dendritic Spines in a Model of Alzheimer's Disease. Cerebral Cortex 19 586 592 18632740
- [30]Grutzendler J Helmin K Tsai J Gan WB 2007 Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer's disease. Ann. N Y Acad. Sci 1097 30 39 17413007
- [32]Brion JP Couck AM Passareiro E Flamentdurand J 1985 Neurofibrillary Tangles of Alzheimers-Disease - An Immunohistochemical Study. Journal of Submicroscopic Cytology and Pathology 17 89 96 3973960
- [33]Grundke-Iqbal I Iqbal K Tung YC Quinlan M Wisniewski HM 1986 Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83 4913 4917 3088567 PMC323854
- [34]Goedert M Wischik CM Crowther RA Walker JE Klug A 1988 Cloning and Sequencing of the Cdna-Encoding A Core Protein of the Paired Helical Filament of Alzheimer-Disease - Identification As the Microtubule-Associated Protein Tau. Proceedings of the National Academy of Sciences of the United States of America 85 4051 4055 3131773 PMC280359
- [35]Terry RD Peck A DeTeresa R Schechter R Horoupian DS 1981 Some Morphometric Aspects of the Brain in Senile Dementia of the Alzheimer Type. Ann Neurol 10 184 192 7283403
- [37]Feng G Mellor RH Bernstein M Keller-Peck C Nguyen QT 2000 Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28 41 51 11086982
- [39]Trachtenberg JT Chen BE Knott GW Feng G Sanes JR 2002 Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420 788 794 12490942
- [41]Holtmaat A Wilbrecht L Knott GW Welker E Svoboda K 2006 Experience-dependent and cell-type-specific spine growth in the neocortex. Nature 441 979 983 16791195
- [42]Fuhrmann M Mitteregger G Kretzschmar H Herms J 2007 Dendritic pathology in prion disease starts at the synaptic spine. J Neurosci 27 6224 6233 17553995 PMC6672160
- [44]Holtmaat A Bonhoeffer T Chow DK Chuckowree J De Paola V 2009 Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nature Protocols 4 1128 1144 19617885 PMC3072839
- [45]Fuhrmann M Bittner T Jung CKE Burgold S Page RM Mitteregger 2010 Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nature Neuroscience 13 411 413 20305648 PMC4072212
- [46]Horn G Bradley P McCabe BJ 1985 Changes in the Structure of Synapses Associated with Learning. J Neurosci 5 3161 3168 4078621 PMC6565237
- [47]Moser MB Trommald M Andersen P 1994 An Increase in Dendritic Spine Density on Hippocampal Ca1 Pyramidal Cells Following Spatial-Learning in Adult-Rats Suggests the Formation of New Synapses. Proceedings of the National Academy of Sciences of the United States of America 91 12673 12675 7809099 PMC45501
- [48]Segal M 2002 Dendritic spines: elementary structural units of neuronal plasticity. Plasticity in the Adult Brain: from Genes to Neurotherapy 138 53 59 12432762
- [50]Gogolla N Galimberti I DePaola V Caroni P 2006 Staining protocol for organotypic hippocampal slice cultures. Nature Protocols 1 2452 2456 17406491
- [51]Holtmaat AJ Trachtenberg JT Wilbrecht L Shepherd GM Zhang X 2005 Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45 279 291 15664179
- [52]Knott GW Holtmaat A Wilbrecht L Welker E Svoboda K 2006 Spine growth precedes synapse formation in the adult neocortex in vivo. Nature Neuroscience 9 1117 1124 16892056
- Authors
- Bittner, T., Fuhrmann, M., Burgold, S., Ochs, S. M., Hoffmann, N., Mitteregger, G., Kretzschmar, H., LaFerla, F. M., & Herms, J.
- Affiliations
- Institut für Neuropathologie (DE)
- University of California, Irvine (US)
- Corresponding author
- Herms, Jochen
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-11-16
- Volume
- 5
- Issue
- 11
- Pages
- e15477
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2982845
- OpenAlex
- W2068883870
- Cited by
- 149
- References
- 54
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 7 · 2023: 10 · 2022: 2 · 2021: 11 · 2020: 14 · 2019: 7 · 2018: 8 · 2017: 12 · 2016: 10 · 2015: 6 · 2014: 15 · 2013: 19 · 2012: 15
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- University of Pittsburgh
- European Commission (Neuro.GSK3, 223276)
- Deutsche Forschungsgemeinschaft (SFB 596)
- Bundesministerium für Bildung und Forschung (01GZ0713)
- Bundesministerium für Wirtschaft und Technologie (16IN0675)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, dendritic spine loss, 3xTg-AD mice, amyloid-beta, hyperphosphorylated tau, amyloid plaques, synaptic loss, soluble amyloid-beta, fibrillar amyloid-beta
- MeSH terms
- Alzheimer Disease, Animals, Brain Diseases, Female, Frontal Lobe, Hippocampus, Immunohistochemistry, Male, Mice, Transgenic, Mutation, Neurons, Somatosensory Cortex, Time Factors, Amyloid beta-Protein Precursor, tau Proteins, Microscopy, Confocal, Amino Acid Substitution, Dendritic Spines, Mice, Presenilin-1, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
