June 7, 2021
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Article

Three-dimensional analysis of synaptic organization in the hippocampal CA1 field in Alzheimer's disease

Publicated to: BRAIN. 144 (2): 553-573 - 2021-03-03 144(2), DOI: 10.1093/brain/awaa406

Authors:

Montero-Crespo, M; Domínguez-Alvaro, M; Alonso-Nanclares, L; DeFelipe, J; Blazquez-Llorca, L
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Affiliations

CSIC, Inst Cajal, Av Doctor Arce 37, Madrid 28002, Spain - Author
ISCIII, Ctr Invest Biomed Red Enfermedades Neurodegenerat, C Valderrebollo 5, Madrid 28031, Spain - Author
Univ Complutense Madrid, Fac Vet, Secc Dept Anat & Embriol Vet, Av Puerta de Hierro S-N, Madrid 28040, Spain - Author
Univ Nacl Educ Distancia UNED, Fac Psicol, Dept Psicobiol, C Juan del Rosal 10, Madrid 28040, Spain - Author
Univ Politecn Madrid, Ctr Tecnol Biomed, Lab Cajal Circuitos Cort, Madrid 28223, Spain - Author
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Abstract

Alzheimer's disease is the most common form of dementia, characterized by a persistent and progressive impairment of cognitive functions. Alzheimer's disease is typically associated with extracellular deposits of amyloid-beta peptide and accumulation of abnormally phosphorylated tau protein inside neurons (amyloid-beta and neurofibrillary pathologies). It has been proposed that these pathologies cause neuronal degeneration and synaptic alterations, which are thought to constitute the major neurobiological basis of cognitive dysfunction in Alzheimer's disease. The hippocampal formation is especially vulnerable in the early stages of Alzheimer's disease. However, the vast majority of electron microscopy studies have been performed in animal models. In the present study, we performed an extensive 3D study of the neuropil to investigate the synaptic organization in the stratum pyramidale and radiatum in the CA1 field of Alzheimer's disease cases with different stages of the disease, using focused ion beam/scanning electron microscopy (FIB/SEM). In cases with early stages of Alzheimer's disease, the synapse morphology looks normal and we observed no significant differences between control and Alzheimer's disease cases regarding the synaptic density, the ratio of excitatory and inhibitory synapses, or the spatial distribution of synapses. However, differences in the distribution of postsynaptic targets and synaptic shapes were found. Furthermore, a lower proportion of larger excitatory synapses in both strata were found in Alzheimer's disease cases. Individuals in late stages of the disease suffered the most severe synaptic alterations, including a decrease in synaptic density and morphological alterations of the remaining synapses. Since Alzheimer's disease cases show cortical atrophy, our data indicate a reduction in the total number (but not the density) of synapses at early stages of the disease, with this reduction being much more accentuated in subjects with late stages of Alzheimer's disease. The observed synaptic alterations may represent a structural basis for the progressive learning and memory dysfunctions seen in Alzheimer's disease cases.
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Keywords

amyloid-betacerebral-cortexdendritic spinesdentate gyruselectron microscopyentorhinal cortexfib/semhippocampusneurovascular dysfunctionpyramidal neuronsquantitative assessmentspatial-distributionsynapsesAlzheimer diseaseAmyloid-betaCa1 region, hippocampalCerebral-cortexDementiaDendritic spinesDentate gyrusElectron microscopyFemaleFibFib/semFib/sem technologyHippocampusHumansImaging, three-dimensionalMaleMicroscopy, electron, scanningMild cognitive impairmentNeurofibrillary tanglesNeuronsNeurovascular dysfunctionQuantitative assessmentSemSpatial-distributionSynapses

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal BRAIN due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 6/212, thus managing to position itself as a Q1 (Primer Cuartil), in the category Clinical Neurology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 4.48. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 13, 2025)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 4.89 (source consulted: FECYT Mar 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2026-04-27, the following number of citations:

  • WoS: 55
  • Scopus: 65
  • Europe PMC: 37
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-04-27:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 91.

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 33.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 40 (Altmetric).
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://oa.upm.es/85544/

As a result of the publication of the work in the institutional repository, statistical usage data has been obtained that reflects its impact. In terms of dissemination, we can state that, as of

  • Views: 283
  • Downloads: 167
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Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Montero-Crespo, M) and Last Author (Blázquez Llorca, Lidia).

the author responsible for correspondence tasks has been Blázquez Llorca, Lidia.

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Awards linked to the item

This study was funded by grants from the Spanish Ministerio de Ciencia e Innovacion (grant PGC2018-094307-B-I00), Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain, CB06/05/0066), the Alzheimer's Association (ZEN-15-321663) and the Universidad Nacional de Educacion a Distancia (UNED, Spain, Plan de Promocion de la Investigacion, 2014-040-UNED-POST). M.M-C. was awarded a research fellowship from the Spanish Ministerio de Educacion, Cultura y Deporte (contract FPU14/02245).
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