Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies
Abstract
Synapse loss precedes cell death in Alzheimer's disease, but the timing of axon degeneration relative to these events, and the causal relationships remain unclear. Axons become so severely dystrophic near amyloid plaques that their interruption, causing permanent loss of function, extensive synapse loss, and potentially cell death appears imminent. However, it remains unclear whether axons are truly interrupted at plaques and whether cell bodies fail to support their axons and dendrites. We traced TgCRND8 mouse axons longitudinally through, distal to, and proximal from dystrophic regions. The corresponding neurons not only survived but remained morphologically unaltered, indicating absence of axonal damage signalling or a failure to respond to it. Axons, no matter how dystrophic, remained continuous and initially morphologically normal outside the plaque region, reflecting support by metabolically active cell bodies and continued axonal transport. Immunochemical and ultrastructural studies showed dystrophic axons were tightly associated with disruption of presynaptic transmission machinery, suggesting local functional impairment. Thus, we rule out long-range degeneration axons or dendrites as major contributors to early synapse loss in this model, raising the prospect of a therapeutic window for functional rescue of individual neurons lasting months or even years after their axons become highly dystrophic. We propose that multi-focal pathology has an important role in the human disease in bringing about the switch from local, and potentially recoverable, synapse loss into permanent loss of neuronal processes and eventually their cell bodies.
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Disruption of fast axonal transport results in focal swellings filled with organelles in AD transgenic models, resembling Wallerian degeneration.
“Another important factor might be the disruption of fast axonal transport, resulting in focal swellings filled with various organelles, as seen in the vicinity but also distant from plaques in several AD transgenic models [27,28,29,30], resembling Wallerian degeneration [31].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [27]
CRND8 APP mice reveal reduced synaptic markers and hippocampal neuronal loss at 6 months, when overlaps are first detected with cluster B modules.
“CRND8 APP mice reveal reduced synaptic markers and hippocampal neuronal loss at 6 months, when overlaps are first detected with cluster B modules (Adalbert et al., 2009; Brautigam et al., 2012).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Adalbert et al., 2009
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- Authors
- Adalbert, R., Nogradi, A., Babetto, E., Janeckova, L., Walker, S. A., Kerschensteiner, M., Misgeld, T., & Coleman, M. P.
- Affiliations
- Babraham Institute (GB)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-12-05
- Volume
- 132
- Issue
- 2
- Pages
- 402-416
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2161240378
- Cited by
- 177
- References
- 60
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 15 · 2021: 9 · 2020: 11 · 2019: 10 · 2018: 5 · 2017: 9 · 2016: 16 · 2015: 10 · 2014: 6 · 2013: 12 · 2012: 21
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (069652/Z/02/Z)
- Biotechnology and Biological Sciences Research Council
- 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, axonal dystrophy, amyloid plaques, synaptic loss, axonal degeneration, axonal transport, neuronal survival, therapeutic window
- MeSH terms
- Alzheimer Disease, Animals, Axons, Breeding, Cell Survival, Immunohistochemistry, Male, Mice, Inbred C57BL, Microscopy, Electron, Nerve Degeneration, Synaptic Transmission, Neurons, Models, Animal, Mice, Plaque, Amyloid
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