High plasticity of axonal pathology in Alzheimer's disease mouse models.
Axonal dystrophies (AxDs) are swollen and tortuous neuronal processes that are associated with extracellular depositions of amyloid β (Aβ) and have been observed to contribute to synaptic alterations occurring in Alzheimer's disease. Understanding the temporal course of this axonal pathology is of high relevance to comprehend the progression of the disease over time. We performed a long-term in vivo study (up to 210 days of two-photon imaging) with two transgenic mouse models (dE9xGFP-M and APP-PS1xGFP-M). Interestingly, AxDs were formed only in a quarter of GFP-expressing axons near Aβ-plaques, which indicates a selective vulnerability. AxDs, especially those reaching larger sizes, had long lifetimes and appeared as highly plastic structures with large variations in size and shape and axonal sprouting over time. In the case of the APP-PS1 mouse only, the formation of new long axonal segments in dystrophic axons (re-growth phenomenon) was observed. Moreover, new AxDs could appear at the same point of the axon where a previous AxD had been located before disappearance (re-formation phenomenon). In addition, we observed that most AxDs were formed and developed during the imaging period, and numerous AxDs had already disappeared by the end of this time. This work is the first in vivo study analyzing quantitatively the high plasticity of the axonal pathology around Aβ plaques. We hypothesized that a therapeutically early prevention of Aβ plaque formation or their growth might halt disease progression and promote functional axon regeneration and the recovery of neural circuits.
German Center for Neurodegenerative Diseases-Munich site (DZNE-M) and Center for Neuropathology and Prion Research (ZNP), Ludwig-Maximilians University, Munich, Feodor-Lynen-St 23, 81377, Munich, Germany. lblazquez@psi.uned.es.|Departmento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), C/Juan del Rosal 10, 28040, Madrid, Spain. lblazquez@psi.uned.es.
Lidia
http://orcid.org/0000-0002-4865-8974
L
Blazquez-Llorca
German Center for Neurodegenerative Diseases-Munich site (DZNE-M) and Center for Neuropathology and Prion Research (ZNP), Ludwig-Maximilians University, Munich, Feodor-Lynen-St 23, 81377, Munich, Germany.
Susana
S
Valero-Freitag
German Center for Neurodegenerative Diseases-Munich site (DZNE-M) and Center for Neuropathology and Prion Research (ZNP), Ludwig-Maximilians University, Munich, Feodor-Lynen-St 23, 81377, Munich, Germany.
Eva Ferreira
EF
Rodrigues
Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Madrid, Spain.|Departamento de Arquitectura y Tecnología de Sistemas Informáticos, Escuela Técnica Superior de Ingenieros Informáticos, Universidad Politécnica de Madrid, Madrid, Spain.
Ángel
Á
Merchán-Pérez
Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Madrid, Spain.|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
J Rodrigo
JR
Rodríguez
German Center for Neurodegenerative Diseases-Munich site (DZNE-M) and Center for Neuropathology and Prion Research (ZNP), Ludwig-Maximilians University, Munich, Feodor-Lynen-St 23, 81377, Munich, Germany.
Mario M
MM
Dorostkar
Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Madrid, Spain.|Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.
Javier
J
DeFelipe
German Center for Neurodegenerative Diseases-Munich site (DZNE-M) and Center for Neuropathology and Prion Research (ZNP), Ludwig-Maximilians University, Munich, Feodor-Lynen-St 23, 81377, Munich, Germany. Jochen.Herms@med.uni-muenchen.de.|Munich Cluster of Systems Neurology (SyNergy), Ludwig-Maximilians University, Munich, Germany. Jochen.Herms@med.uni-muenchen.de.
Jochen
J
Herms
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D048429:Cell Size; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009473:Neuronal Plasticity; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D013003:Somatosensory Cortex / Q000378:metabolism / Q000473:pathology*
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D049452:Green Fluorescent Proteins
Alzheimer’s disease; Dystrophic neurites; FIB/SEM microscopy; Three-dimensional; Two-photon microscopy