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Cited by 235Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

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Dorostkar, Mario M., Zou, Chengyu, Blazquez-Llorca, Lidia, Herms, Jochen·2015·Acta Neuropathologica
DOI 10.1007/s00401-015-1449-5PMC PMC4469300
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Abstract

Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer's disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer's disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer's disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer's disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer's disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder.

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Fig. 1 Dendritic spines are remodeled in enriched environment. a Chronic in vivo imaging of the same apical dendrites from layer V pyramidal neurons in the somatosensory cortex over 43 days when GFP-M mice were housed in standard conditions (SC) or enriched environment (EE). Blue and green arrowheads point to preexisting spines which are shown in the first image and new-gained spines that emerged over two consecutive imaging sessions, respectively. Empty arrowheads indicate the lost preexisting spines (blue) and new-gained spines (green). The images show high-contrast representations of maximum-intensity projected multiphoton images. b Graphical representations of the relative spine density. c, d The fate of preexisting spines in the first imaging time point and new-gained spines at the second imaging time point. e Apical dendrites (black) from layer V pyramidal neurons housed in SC or EE and 3D reconstructions (gray) generated in Imaris. The images show high-contrast representations of maximum-intensity projected confocal images. Mushroom, thin and stubby spines are colored in green, blue and red. f Plot of mushroom, thin and stubby spine fractions when mice were exposed to SC or EE. g Cumulative distributions of spine length and head volume when mice were exposed to SC or EE. *p < 0.05, **p < 0.01 (Two-way ANOVA in b–d, Student’s t test in f and Komogornov–Smirnov test in g)
Fig. 1 Dendritic spines are remodeled in enriched environment. a Chronic in vivo imaging of the same apical dendrites from layer V pyramidal neurons in the somatosensory cortex over 43 days when GFP-M mice were housed in standard conditions (SC) or enriched environment (EE). Blue and green arrowheads point to preexisting spines which are shown in the first image and new-gained spines that emerged over two consecutive imaging sessions, respectively. Empty arrowheads indicate the lost preexisting spines (blue) and new-gained spines (green). The images show high-contrast representations of maximum-intensity projected multiphoton images. b Graphical representations of the relative spine density. c, d The fate of preexisting spines in the first imaging time point and new-gained spines at the second imaging time point. e Apical dendrites (black) from layer V pyramidal neurons housed in SC or EE and 3D reconstructions (gray) generated in Imaris. The images show high-contrast representations of maximum-intensity projected confocal images. Mushroom, thin and stubby spines are colored in green, blue and red. f Plot of mushroom, thin and stubby spine fractions when mice were exposed to SC or EE. g Cumulative distributions of spine length and head volume when mice were exposed to SC or EE. *p < 0.05, **p < 0.01 (Two-way ANOVA in b–d, Student’s t test in f and Komogornov–Smirnov test in g)CC BY · PubMed Central
Fig. 2 Putative pathophysiological mechanisms for dendritic spine loss. 1 Fibrillar amyloid plaques cause spine loss in their immediate vicinity. 2 Spine loss at dystrophic dendrites. 3 Secondary spine loss due to presynaptic failure. 4 Amyloid oligomers engaging synaptic targets. 5 Amyloid uptake. 6 Axonal amyloid beta. 7 Hyperphosphorylated tau protein. 8 Deafferentation. 9 NMDA receptor-mediated excitotoxicity. 10 Spine pruning by microglia; Microglia activation leading to release of inflammatory mediators. 11 Immune activation, reactive oxygen species and activation of pro-apoptotic pathways
Fig. 2 Putative pathophysiological mechanisms for dendritic spine loss. 1 Fibrillar amyloid plaques cause spine loss in their immediate vicinity. 2 Spine loss at dystrophic dendrites. 3 Secondary spine loss due to presynaptic failure. 4 Amyloid oligomers engaging synaptic targets. 5 Amyloid uptake. 6 Axonal amyloid beta. 7 Hyperphosphorylated tau protein. 8 Deafferentation. 9 NMDA receptor-mediated excitotoxicity. 10 Spine pruning by microglia; Microglia activation leading to release of inflammatory mediators. 11 Immune activation, reactive oxygen species and activation of pro-apoptotic pathwaysCC BY · PubMed Central
Fig. 3 Neuritic pathology in a mouse model of amyloidosis. Electron micrograph of neuropil in the vicinity of a fibrillar plaque (not shown) of an APPPS1 mouse. Dystrophic axons (labeled “Axon”) appear enlarged and filled with electron-dense membranous material. Several synaptic densities are marked with arrows. Note that most synapses originate from unaltered synaptic boutons, while only a single synapse originates from the dystrophic axon (double arrow, far right), which may reflects spine loss as a result of presynaptic failure
Fig. 3 Neuritic pathology in a mouse model of amyloidosis. Electron micrograph of neuropil in the vicinity of a fibrillar plaque (not shown) of an APPPS1 mouse. Dystrophic axons (labeled “Axon”) appear enlarged and filled with electron-dense membranous material. Several synaptic densities are marked with arrows. Note that most synapses originate from unaltered synaptic boutons, while only a single synapse originates from the dystrophic axon (double arrow, far right), which may reflects spine loss as a result of presynaptic failureCC BY · PubMed Central
Fig. 4 Spine loss is observed on dendrites that are close to amyloid plaques. a GFP-labeled dendrites (black) and methoxy-X04-labeled amyloid plaques (blue) from APPPS1xGFP-M mice. The images show high-contrast representations of maximum-intensity projected multiphoton images. Black arrowheads point to dendrites that are located close (<30 µm) to or far from (>100 µm) plaques, which are shown enlarged in b. b Maximum intensity projected apical dendrites that are located close (<30 µm) to or far from (>100 µm) amyloid plaques. The same dendrites were repeatedly imaged 1 week apart. Red arrowheads point at spines eliminated over 1 week and green arrowheads point at newly formed spines. c Spine densities of apical dendrites on different localizations (>100 or <30 µm from plaques). Spines that were new-gained d or lost e over 1 week on dendrites (>100 or <30 µm from amyloid plaques). *p < 0.05, **p < 0.01 (Student’s t test)
Fig. 4 Spine loss is observed on dendrites that are close to amyloid plaques. a GFP-labeled dendrites (black) and methoxy-X04-labeled amyloid plaques (blue) from APPPS1xGFP-M mice. The images show high-contrast representations of maximum-intensity projected multiphoton images. Black arrowheads point to dendrites that are located close (<30 µm) to or far from (>100 µm) plaques, which are shown enlarged in b. b Maximum intensity projected apical dendrites that are located close (<30 µm) to or far from (>100 µm) amyloid plaques. The same dendrites were repeatedly imaged 1 week apart. Red arrowheads point at spines eliminated over 1 week and green arrowheads point at newly formed spines. c Spine densities of apical dendrites on different localizations (>100 or <30 µm from plaques). Spines that were new-gained d or lost e over 1 week on dendrites (>100 or <30 µm from amyloid plaques). *p < 0.05, **p < 0.01 (Student’s t test)CC BY · PubMed Central
Fig. 5 The content of intraneuronal APP is negatively correlated with spine density. a APP accumulation in GFP expressing layer V pyramidal neurons from APP23 mice (top). Dendrites that originated from the soma are shown below as high-contrast representations of maximum-intensity projected confocal images. b The dot plot is the corrected intensity of intercellular APP vs. spine density. Straight line is fitted by nonlinear regression. **p < 0.01 (F test). Figure adapted from Ref. [228]
Fig. 5 The content of intraneuronal APP is negatively correlated with spine density. a APP accumulation in GFP expressing layer V pyramidal neurons from APP23 mice (top). Dendrites that originated from the soma are shown below as high-contrast representations of maximum-intensity projected confocal images. b The dot plot is the corrected intensity of intercellular APP vs. spine density. Straight line is fitted by nonlinear regression. **p < 0.01 (F test). Figure adapted from Ref. [228]CC BY · PubMed Central

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Metadata

Authors
Dorostkar, M. M., Zou, C., Blazquez-Llorca, L., & Herms, J.
Affiliations
  • Institut für Neuropathologie (DE)
  • German Center for Neurodegenerative Diseases (DE)
Corresponding author
Herms, Jochen
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2015-06-11
Volume
130
Issue
1
Pages
1-19
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-015-1449-5
PMC
PMC4469300
OpenAlex
W622376569
Cited by
235
References
232
Citations by year
2026: 15 · 2025: 30 · 2024: 34 · 2023: 20 · 2022: 25 · 2021: 29 · 2020: 23 · 2019: 19 · 2018: 13 · 2017: 13 · 2016: 12 · 2015: 2
FWCI
1.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DZNE Pub (submittedVersion, cc-by)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
dendritic spine loss, Alzheimer's disease, synaptic dysfunction, amyloid-beta, amyloid oligomers, tau hyperphosphorylation, microglial activation, animal models of Alzheimer's disease, cognitive decline, memory impairment
MeSH terms
Alzheimer Disease, Amyloid, Animals, Brain, Humans, Dendritic Spines

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