Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease

By T. Kawarabayashi, L. Younkin, T. Saido, M. Shoji, K. Ashe, S. Younkin. Journal of Neuroscience, 2001

926 citations recorded by the source corpus.

The accumulation of amyloid β protein (Aβ) in the Tg2576 mouse model of Alzheimer's disease (AD) was evaluated by ELISA, immunoblotting, and immunocytochemistry. Changes in Aβ begin at 6–7 months as SDS-insoluble forms of Aβ42 and Aβ40 that require formic acid for solubilization appear. From 6 to 10 months, these insoluble forms increase exponentially. As insoluble Aβ appears, SDS-soluble Aβ decreases slightly, suggesting that it may be converting to an insoluble form. Our data indicate that it is full-length unmodified Aβ that accumulates initially in Tg2576 brain. SDS-resistant Aβ oligomers and most Aβ species that are N-terminally truncated or modified develop only in older Tg2576 mice, in which they are present at levels far lower than in human AD brain. Between 6 and 10 months, when SDS-insoluble Aβ42 and Aβ40 are easily detected in every animal, histopathology is minimal because only isolated Aβ cores can be identified. By 12 months, diffuse plaques are evident. From 12 to 23 months, diffuse plaques, neuritic plaques with amyloid cores, and biochemically extracted Aβ42 and Aβ40 increase to levels like those observed in AD brains. Coincident with the marked deposition of Aβ in brain, there is a decrease in CSF Aβ and a substantial, highly significant decrease in plasma Aβ. If a similar decline occurs in human plasma, it is possible that measurement of plasma Aβ may be useful as a premorbid biomarker for AD.

Subfields: Computational Theory and Mathematics, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/3ed4c46400edeece515c7a23e469e89c233699f5

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In Computational Theory and Mathematics

1. Berislav Zlokovic
2. K. Ashe
3. D. Holtzman
4. C. Iadecola
5. M. Beal

In Molecular Biology

1. P. Tontonoz
2. C. Iadecola
3. Berislav Zlokovic
4. D. Holtzman
5. R. Deane
6. Nancy A. Jenkins
7. N. Zelcer
8. C. Kenyon

In Physiology

1. Berislav Zlokovic
2. D. Holtzman
3. C. Iadecola
4. R. Deane
5. Bradley T. Hyman
6. M. Finn
7. C. Kenyon
8. K. Ashe

Citations in the corpus

• Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis (2001, background): “Indeed, the recent demonstration of rare Ab plaques as well as scant amounts of formic acid-extractable Ab in 8-month-old Tg2576 mouse brains prompts cautious interpretation of our data with respect to whether LPO precedes or is linked to the initial stages of AD-like amyloidosis in Tg2576 mice ( Ka”
• Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. (2005, background): “Data represent mean 6 SEM. in humans, results in early onset, familial AD and develop Ab deposition in amyloid plaques beginning at about 8–9 months of age (Kawarabayashi et al., 2001).”
• The Relationship between Aβ and Memory in the Tg2576 Mouse Model of Alzheimer's Disease (2002, methodology): “Punctate A deposits much smaller and sparser than mature plaques appear at 6–8 months, whereas amyloid plaques appear at 9–12 months and increase to numbers similar to those seen in Alzheimer’s patients by 16–20 months (Irizarry et al., 1997; Kawarabayashi et al., 2001).”
• Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase (2004, methodology): “Brain extracts were measured by sandwich ELISA as described previously (11, 58 ,76).”
• Widespread Protein Aggregation as an Inherent Part of Aging in C. elegans (2010, background): “Proteins known to aggregate in disease, such as tau protein and amyloid-b, remain insoluble in strong-detergent buffers [21,22,23] but can be solubilized by formic acid or urea and analyzed on SDS-PAGE gels.”
• A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity (2001, background): “Ibuprofen treatment of Tg2576 transgenic mice Female Tg2576 mice overexpressing APP695 containing the ‘Swedish’ mutation were treated at 3 months old, when they show high levels of soluble Aβ in brain but no signs of Aβ depositio”
• Neurovascular regulation in the normal brain and in Alzheimer's disease (2004, background): “Transgenic mice overexpressing the SWEDISH MUTATION of App develop cognitive impairment at 6 months of age and amyloid plaques at 9–12 month”
• Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model (2007, methodology): “hemispheres using colorimetric ELISA kits as previously described (Kawarabayashi et al. 2001) with minor modifications.”
• RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain (2003, background): “Here we show that RAGE contributes to transport of pathophysiologically relevant concentrations of Aβ into the CNS, comparable to the baseline plasma levels of Aβ in Tg2576 (ref”
• ApoE promotes the proteolytic degradation of Abeta. (2008, background): “, 1995) and exhibit extensive deposits of Aβ by one year of age (Kawarabayashi et al., 2001).”