Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer’s Disease
Abstract
We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.
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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 [28]
Tg-swAPP Prp commonly exhibited axonal blockages that were not immunoreactive for ChAT and occasionally displayed electron dense axoplasm reminiscent of axonal degeneration.
“As previously reported (7), Tg-swAPP Prp commonly exhibited axonal blockages that were not immunoreactive for ChAT and occasionally displayed electron dense axoplasm reminiscent of axonal degeneration”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [7]
Overexpression of WT APP or APP bearing FAD mutations in Drosophila and mice can cause impaired axonal transport and axonal defects.
“Intriguingly, recent work revealed that overexpression of WT APP or APP bearing FAD mutations in Drosophila and mice can cause impaired axonal transport and axonal defects (7,8,29,30).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [7]
Single transgenic Tg-swAPP Prp mice had a significantly higher percentage of ChAT-IR fibers with varicosities having diameters between 2.7 and 3.6 mm, 3.6 and 4.5 mm and larger than 4.5 mm compared with WT littermates in both genetic backgrounds examined.
“As reported previously (7), single transgenic Tg-swAPP Prp mice had a significantly higher percentage of choline acetyltransferase-immunoreactive (ChAT-IR) fibers with varicosities having diameters between 2.7 and 3.6 mm, 3.6 and 4.5 mm and larger than 4.5 mm compared with WT littermates in both genetic backgrounds examined”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [7]
Formation of these defects was enhanced by genetic reductions in kinesin-1 in Drosophila and in mice, where increased Aβ42/Aβ40 ratios and enhanced amyloid deposition were also observed.
“Formation of these defects was shown to be enhanced by genetic reductions in kinesin-1 in Drosophila (29,30) and in mice, where increased Ab42/Ab40 ratios and enhanced amyloid deposition were also observed (7,57).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [7]
In both Drosophila and mice, APP-mediated axonal transport defects can be enhanced by genetic reductions in kinesin-I.
“In fact, in both Drosophila and mice, APP-mediated axonal transport defects can be enhanced by genetic reductions in kinesin-I (7,29,30).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [7]
Large diameter axonal varicosities correspond to axonal swellings, a bona fide equivalent of axonal blockages at the light microscope level.
“Since previous work on cholinergic fibers in the BN found that large diameter axonal varicosities correspond to axonal swellings, a bona fide equivalent of axonal blockages at the light microscope level (7), we measured diameters and lengths of varicosities and inter-varicosity shafts”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [7]
Axonal blockages in Drosophila and mice are thought to correspond to aberrant accumulations of proteins, vesicles and organelles within axons that block or otherwise inhibit normal axonal transport.
“Axonal blockages in Drosophila and mice are thought to correspond to aberrant accumulations of proteins, vesicles and organelles within axons that block or otherwise inhibit normal axonal transport (7,29,(48)(49)(50)(51).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [7]
Genetic reductions in kinesin-I also enhanced aberrant Aβ generation and amyloid deposition.
“These reductions also enhanced aberrant Ab generation and amyloid deposition (7).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [7]
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Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
- Authors
- Stokin, G. B., Lillo, C., Falzone, T. L., Brusch, R. G., Rockenstein, E., Mount, S. L., Raman, R., Davies, P., Masliah, E., Williams, D. S., & Goldstein, L. S. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
- Corresponding author
- Goldstein, Lawrence S. B.
- ORCID
- Venue
- Science
- Published
- 2005-02-25
- Volume
- 307
- Issue
- 5713
- Pages
- 1282-1288
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2171776741
- Cited by
- 1,214
- References
- 38
- Citations by year
- 2026: 28 · 2025: 37 · 2024: 47 · 2023: 37 · 2022: 43 · 2021: 54 · 2020: 47 · 2019: 45 · 2018: 46 · 2017: 47 · 2016: 59 · 2015: 51 · 2014: 61 · 2013: 58 · 2012: 81
- FWCI
- 48.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30ey012598-05)
- National Institute on Aging (P50AG005131)
- National Eye Institute (EY13408, R01EY013408, EY 12598, R01EY007042)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, axonal swellings, kinesin, microtubule-associated proteins, molecular motors, amyloid-beta, amyloid deposition, amyloid plaques, mouse model
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Axons, Axonal Transport, Brain, Cells, Cultured, Female, Hippocampus, Humans, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Microtubule-Associated Proteins, Neurons, Time Factors, Organelles, Amyloid beta-Peptides, Kinesins, Amyloid beta-Protein Precursor, Basal Nucleus of Meynert, Cytoplasmic Vesicles, Mice, Plaque, Amyloid
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