Brain Trauma in Aged Transgenic Mice Induces Regression of Established Aβ Deposits
Abstract
Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known if TBI affects the progression of AD. To address this question, we studied the neuropathological consequences of TBI in transgenic (TG) mice with a mutant human Abeta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter resulting in overexpression of mutant APP (V717F), elevated brain Abeta levels, and AD-like amyloidosis. Since brain Abeta deposits first appear in 6-month-old TG (PDAPP) mice and accumulate with age, 2-year-old PDAPP and wild-type (WT) mice were subjected to controlled cortical impact (CCI) TBI or sham treatment. At 1, 9, and 16 weeks after TBI, neuron loss, gliosis, and atrophy were most prominent near the CCI site in PDAPP and WT mice. However, there also was a remarkable regression in the Abeta amyloid plaque burden in the hippocampus ipsilateral to TBI compared to the contralateral hippocampus of the PDAPP mice by 16 weeks postinjury. Thus, these data suggest that previously accumulated Abeta plaques resulting from progressive amyloidosis in the AD brain also may be reversible.
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CCI TBI in aged PDAPP mice caused a regression of established Aβ deposits.
“Follow-up experiments revealed that CCI TBI in aged PDAPP mice caused a regression of established Aβ deposits (41).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [41]
Several experimental studies have failed to show that TBI induces or worsens AD-related pathology, with some even reporting a reduction in post-injury Aβ accumulation in transgenic mice.
“Finally, several experimental studies have failed to show that TBI induces or worsens AD-related pathology (38, 39) with some even reporting a reduction in post-injury Aβ accumulation in transgenic mice (40, 41).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [41]
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“Moreover, when 22–24 months old PDAPP mice with abundant β-amyloid plaques were subjected to CCI, the Aβ burden in the ipsilateral hippocampus at 16 weeks post-CCI was reduced as compared to contralateral site [28].”
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“2 m/s; depth = 1 mm) — 24 months Increased hippocampal neuronal loss and gliosis Regression of Aβ in the hippocampus Not measured [157]”
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“These questions are of particular importance given the epidemiology of TBI.”
BackgroundInfluentialLong-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer’s Disease
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“2 m/s; depth = 1 mm) — 24 months Increased hippocampal neuronal loss and gliosis Regression of Aβ in the hippocampus Not measured [157]”
BackgroundVaccines for Alzheimer??s Disease
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Crawford, F., Wood, M., Ferguson, S., Mathura, V. S., Faza, B., Wilson, S., Fan, T., O'Steen, B. E., Ait‐Ghezala, G., Hayes, R. L., et al. (2007) · Brain Research · doi:10.1016/j.brainres.2007.09.042 · Cited by 20 · see citing works
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“95 Therefore, there is a pressing need to carefully consider the utility, development, and standardization of models for the study of neurodegeneration after TBI.”
Models of Traumatic Brain Injury in Aged Animals: A Clinical Perspective
Iboaya, A., Harris, J. L., Arickx, A., & Nudo, R. J. (2019) · Neurorehabilitation and neural repair · doi:10.1177/1545968319883879 · Cited by 20 · see citing works
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Jaisa-aad, M., Muñoz-Castro, C., & Serrano-Pozo, A. (2024) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001243 · Cited by 17 · see citing works
Modelling physical resilience in ageing mice
Schosserer, M., Banks, G. T., Doğan, S., Dungel, P., Fernandes, A. M. A., Marolt, D., Matheu, A., Osuchowski, M. F., Potter, P. K., Sanfeliu, C., et al. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2018.10.001 · Cited by 19 · see citing works
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“Two year-old PDAPP mice, with existing Aβ plaques, given CCI (5 m/s, 1mm depth) actually exhibited a decline in Aβ plaques following injury (Nakagawa et al., 2000).”
BackgroundAge Moderates the Effects of Traumatic Brain Injury on Beta-Amyloid Plaque Load in APP/PS1 Mice
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The Parietal Atrophy Score on Brain Magnetic Resonance Imaging is a Reliable Visual Scale
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“[19] Nakagawa Y, Reed L, Nakamura M, McIntosh TK, Smith DH, Saatman KE, et al.”
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“The H4 receptor (H4R) [Nakagawa et al., 2000] is less widely expressed than other histamine receptors.”
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“…et al., 2015 hTau FPI 2 months 3 days, 135 days ↓Microglial reactivity Kokiko-Cochran et al., 2017 PDAPP CCI 2 year 1, 9, 16 weeks ↓In Aβ deposits ↑neuronal loss at 16 weeks Nakagawa et al., 2000 PDAPP CCI 3–4 months 2 weeks ↑Cognitive dysfunction Brody and Holtzman, 2006 PDAPP CCI 4 months…”
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“Further, Nakagawa et al. observed regression of Aβ plaques in PDAPP mice months following CCI (Nakagawa et al., 1999; Nakagawa et al., 2000).”
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“In addition to pioneering a particular therapeutic regimen, these studies were important in that they established that AD amyloid deposits, long-regarded as insoluble and metabolically inert, are in fact labile, as now confirmed by the use of other experimental paradigms (Nakagawa et al. 2000).”
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“For instance, reduced amyloid plaques below basal level have been reported in several transgenic APP mouse strains after receiving TBI at or beyond 6 months of age by using the controlled cortical impact, 96 the lateral fl uid percussion injury, 97 and the CHIMERA.”
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Cognitive Characteristics of TgAPP CRND8 Mice Immunised with Beta Amyloid Peptide
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- Authors
- Nakagawa, Y., Reed, L., Nakamura, M., McIntosh, T. K., Smith, D. H., Saatman, K. E., Raghupathi, R., Clemens, J., Saido, T. C., Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- Kyushu University (JP)
- University of Pennsylvania (US)
- Eli Lilly (United States) (US)
- RIKEN (JP)
- ORCID
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2000-05
- Volume
- 163
- Issue
- 1
- Pages
- 244-252
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2004117222
- Cited by
- 91
- References
- 0
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 1 · 2013: 3
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG011542, AG09215, P01AG009215, AG 11542)
- National Institute of General Medical Sciences (R01GM034690, GM34690)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, Alzheimer's disease, amyloid plaques, plaque regression, PDAPP mice, controlled cortical impact, amyloidosis, hippocampus, neuronal loss, gliosis, brain atrophy
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain Injuries, Female, Gliosis, Hippocampus, Humans, Immunohistochemistry, Mice, Transgenic, Mutation, Remission Induction, Amyloid beta-Peptides, Head Injuries, Closed, Cell Death, Disease Progression, In Situ Nick-End Labeling, Mice, Plaque, Amyloid
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