Limits...
Impact of amyloid β aggregate maturation on antibody treatment in APP23 mice.

Balakrishnan K, Rijal Upadhaya A, Steinmetz J, Reichwald J, Abramowski D, Fändrich M, Kumar S, Yamaguchi H, Walter J, Staufenbiel M, Thal DR - Acta Neuropathol Commun (2015)

Bottom Line: Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old β1-treated animals sacrificed at 5 months.Aβ antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aβ aggregation was absent or represented B-Aβ stage 1 but had no protective or curative effect in later stages with mature Aβ aggregates (B-Aβ stage 3).These data indicate that the maturation stage of Aβ aggregates has impact on potential treatment effects in APP23 mice.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology - Laboratory of Neuropathology, Center of Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, D-89081, Ulm, Germany.

ABSTRACT

Introduction: The deposition of the amyloid β protein (Aβ) in the brain is a hallmark of Alzheimer's disease (AD). Removal of Aβ by Aβ-antibody treatment has been developed as a potential treatment strategy against AD. First clinical trials showed neither a stop nor a reduction of disease progression. Recently, we have shown that the formation of soluble and insoluble Aβ aggregates in the human brain follows a hierarchical sequence of three biochemical maturation stages (B-Aβ stages). To test the impact of the B-Aβ stage on Aβ immunotherapy, we treated transgenic mice expressing human amyloid precursor protein (APP) carrying the Swedish mutation (KM670/671NL; APP23) with the Aβ-antibody β1 or phosphate-buffered saline (PBS) beginning 1) at 3 months, before the onset of dendrite degeneration and plaque deposition, and 2) at 7 months, after the start of Aβ plaque deposition and dendrite degeneration.

Results: At 5 months of age, first Aβ aggregates in APP23 brain consisted of non-modified Aβ (representing B-Aβ stage 1) whereas mature Aβ-aggregates containing N-terminal truncated, pyroglutamate-modified AβN3pE and phosphorylated Aβ (representing B-Aβ stage 3) were found at 11 months of age in both β1- and PBS-treated animals. Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old β1-treated animals sacrificed at 5 months. When treatment started at 7 months of age, no differences in the numbers of healthy commissural neurons were observed between β1- and PBS-treated APP23 mice sacrificed with 11 months.

Conclusions: Aβ antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aβ aggregation was absent or represented B-Aβ stage 1 but had no protective or curative effect in later stages with mature Aβ aggregates (B-Aβ stage 3). These data indicate that the maturation stage of Aβ aggregates has impact on potential treatment effects in APP23 mice.

No MeSH data available.


Related in: MedlinePlus

Aβ plaque pathology in the frontocentral cortex of APP23 mice: Effects of β1 antibody treatment. Aβ plaque pathology in PBS- and β1-treated APP23 mice. The staining pattern in 11-month-old mice as well as the plaque loads at 5 and 11 months of age did not differ between PBS- and anti-Aβ (β1) treated animals when staining the plaques with antibodies raised against Aβ42 (a–c), Aβ40 (d–f), AβN3pE (g–i), and pAβ (j–l). Graphs c, f, i, and l represent mean values (symbols) and standard errors (whiskers). (Statistical analysis see Additional file 3: Table S3). Calibration bar in a (valid for a, b, d, e, g, h, j, k) = 280 μm
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4491274&req=5

Fig2: Aβ plaque pathology in the frontocentral cortex of APP23 mice: Effects of β1 antibody treatment. Aβ plaque pathology in PBS- and β1-treated APP23 mice. The staining pattern in 11-month-old mice as well as the plaque loads at 5 and 11 months of age did not differ between PBS- and anti-Aβ (β1) treated animals when staining the plaques with antibodies raised against Aβ42 (a–c), Aβ40 (d–f), AβN3pE (g–i), and pAβ (j–l). Graphs c, f, i, and l represent mean values (symbols) and standard errors (whiskers). (Statistical analysis see Additional file 3: Table S3). Calibration bar in a (valid for a, b, d, e, g, h, j, k) = 280 μm

Mentions: Aβ plaques detectable with antibodies directed against Aβ42, Aβ40, Aβ17–24, Aβ1–17, AβN3pE, and pAβ were found in both, β1-treated and PBS-treated APP23 mice (Figs. 2 and 3), without quantitative differences at 5 and 11 months of age, respectively (Additional file 3: Table S3d). At 5 months of age only single plaques in some of the mice were observed whereas in 11-month-old APP23 mice moderate numbers of plaques were seen. Further analysis of 11-month-old animals using the β1 antibody (used for passive immunization) showed that treated animals exhibited fewer plaques stained with β1 indicating epitope masking (Fig. 3 and Additional file 3: Table S3d). B10AP-positive plaques were also reduced in β1-treated 11-month-old animals (Fig. 3) whereas 5-month-old mice did not exhibit B10AP-positive plaques regardless of β1 treatment (Additional file 3: Table S3d). APP-positive dystrophic neurites were seen in APP-type neuritic plaques (i.e. amyloid plaques associated with APP-positive dystrophic neurites) of β1-treated and PBS-treated APP23 mice (Additional file 5: Figure S2). Mouse IgG was not observed in plaques of 5-month-old animals whereas amyloid plaques in 11-month-old β1- and PBS-treated mice exhibited IgG in similar amounts (Additional file 6: Figure S3 and Additional file 7: Figure S4). Plaque-associated astrocytes and microglial cells were seen in both β1- and PBS-treated APP23 mice at 11 months of age whereas no glial reaction was evident in 5-month-old animals (Additional file 6: Figure S3 and Additional file 7: Figure S4).Fig. 2


Impact of amyloid β aggregate maturation on antibody treatment in APP23 mice.

Balakrishnan K, Rijal Upadhaya A, Steinmetz J, Reichwald J, Abramowski D, Fändrich M, Kumar S, Yamaguchi H, Walter J, Staufenbiel M, Thal DR - Acta Neuropathol Commun (2015)

Aβ plaque pathology in the frontocentral cortex of APP23 mice: Effects of β1 antibody treatment. Aβ plaque pathology in PBS- and β1-treated APP23 mice. The staining pattern in 11-month-old mice as well as the plaque loads at 5 and 11 months of age did not differ between PBS- and anti-Aβ (β1) treated animals when staining the plaques with antibodies raised against Aβ42 (a–c), Aβ40 (d–f), AβN3pE (g–i), and pAβ (j–l). Graphs c, f, i, and l represent mean values (symbols) and standard errors (whiskers). (Statistical analysis see Additional file 3: Table S3). Calibration bar in a (valid for a, b, d, e, g, h, j, k) = 280 μm
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4491274&req=5

Fig2: Aβ plaque pathology in the frontocentral cortex of APP23 mice: Effects of β1 antibody treatment. Aβ plaque pathology in PBS- and β1-treated APP23 mice. The staining pattern in 11-month-old mice as well as the plaque loads at 5 and 11 months of age did not differ between PBS- and anti-Aβ (β1) treated animals when staining the plaques with antibodies raised against Aβ42 (a–c), Aβ40 (d–f), AβN3pE (g–i), and pAβ (j–l). Graphs c, f, i, and l represent mean values (symbols) and standard errors (whiskers). (Statistical analysis see Additional file 3: Table S3). Calibration bar in a (valid for a, b, d, e, g, h, j, k) = 280 μm
Mentions: Aβ plaques detectable with antibodies directed against Aβ42, Aβ40, Aβ17–24, Aβ1–17, AβN3pE, and pAβ were found in both, β1-treated and PBS-treated APP23 mice (Figs. 2 and 3), without quantitative differences at 5 and 11 months of age, respectively (Additional file 3: Table S3d). At 5 months of age only single plaques in some of the mice were observed whereas in 11-month-old APP23 mice moderate numbers of plaques were seen. Further analysis of 11-month-old animals using the β1 antibody (used for passive immunization) showed that treated animals exhibited fewer plaques stained with β1 indicating epitope masking (Fig. 3 and Additional file 3: Table S3d). B10AP-positive plaques were also reduced in β1-treated 11-month-old animals (Fig. 3) whereas 5-month-old mice did not exhibit B10AP-positive plaques regardless of β1 treatment (Additional file 3: Table S3d). APP-positive dystrophic neurites were seen in APP-type neuritic plaques (i.e. amyloid plaques associated with APP-positive dystrophic neurites) of β1-treated and PBS-treated APP23 mice (Additional file 5: Figure S2). Mouse IgG was not observed in plaques of 5-month-old animals whereas amyloid plaques in 11-month-old β1- and PBS-treated mice exhibited IgG in similar amounts (Additional file 6: Figure S3 and Additional file 7: Figure S4). Plaque-associated astrocytes and microglial cells were seen in both β1- and PBS-treated APP23 mice at 11 months of age whereas no glial reaction was evident in 5-month-old animals (Additional file 6: Figure S3 and Additional file 7: Figure S4).Fig. 2

Bottom Line: Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old β1-treated animals sacrificed at 5 months.Aβ antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aβ aggregation was absent or represented B-Aβ stage 1 but had no protective or curative effect in later stages with mature Aβ aggregates (B-Aβ stage 3).These data indicate that the maturation stage of Aβ aggregates has impact on potential treatment effects in APP23 mice.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology - Laboratory of Neuropathology, Center of Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, D-89081, Ulm, Germany.

ABSTRACT

Introduction: The deposition of the amyloid β protein (Aβ) in the brain is a hallmark of Alzheimer's disease (AD). Removal of Aβ by Aβ-antibody treatment has been developed as a potential treatment strategy against AD. First clinical trials showed neither a stop nor a reduction of disease progression. Recently, we have shown that the formation of soluble and insoluble Aβ aggregates in the human brain follows a hierarchical sequence of three biochemical maturation stages (B-Aβ stages). To test the impact of the B-Aβ stage on Aβ immunotherapy, we treated transgenic mice expressing human amyloid precursor protein (APP) carrying the Swedish mutation (KM670/671NL; APP23) with the Aβ-antibody β1 or phosphate-buffered saline (PBS) beginning 1) at 3 months, before the onset of dendrite degeneration and plaque deposition, and 2) at 7 months, after the start of Aβ plaque deposition and dendrite degeneration.

Results: At 5 months of age, first Aβ aggregates in APP23 brain consisted of non-modified Aβ (representing B-Aβ stage 1) whereas mature Aβ-aggregates containing N-terminal truncated, pyroglutamate-modified AβN3pE and phosphorylated Aβ (representing B-Aβ stage 3) were found at 11 months of age in both β1- and PBS-treated animals. Protective effects on commissural neurons with highly ramified dendritic trees were observed only in 3-month-old β1-treated animals sacrificed at 5 months. When treatment started at 7 months of age, no differences in the numbers of healthy commissural neurons were observed between β1- and PBS-treated APP23 mice sacrificed with 11 months.

Conclusions: Aβ antibody treatment was capable of protecting neurons from dendritic degeneration as long as Aβ aggregation was absent or represented B-Aβ stage 1 but had no protective or curative effect in later stages with mature Aβ aggregates (B-Aβ stage 3). These data indicate that the maturation stage of Aβ aggregates has impact on potential treatment effects in APP23 mice.

No MeSH data available.


Related in: MedlinePlus