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Amyloid Beta annular protofibrils in cell processes and synapses accumulate with aging and Alzheimer-associated genetic modification.

Kokubo H, Kayed R, Glabe CG, Staufenbiel M, Saido TC, Iwata N, Yamaguchi H - Int J Alzheimers Dis (2009)

Bottom Line: Amyloid beta (Abeta) annular protofibrils (APFs) have been described where the structure is related to that of beta barrel pore-forming bacterial toxins and exhibits cellular toxicity.To investigate the relationship of Abeta APFs to disease and their ultrastructural localization in brain tissue, we conducted a pre-embedding immunoelectron microscopic study using anti-annular protofibril antiserum.We examined brain tissues of young- and old-aged amyloid precursor protein transgenic mice (APP23), neprilysin knockout APP23 mice, and nontransgenic littermates. alphaAPF-immunoreactions tended to be found (1) on plasma membranes and vesicles inside of cell processes, but not on amyloid fibrils, (2) with higher density due to aging, APP transgene, and neprilysin deficiency, and (3) with higher positive rate at synaptic compartments in aged APP23, especially in neprilysin knockout APP23 mice.

View Article: PubMed Central - PubMed

Affiliation: School of Health Sciences, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8514, Japan.

ABSTRACT
Amyloid beta (Abeta) annular protofibrils (APFs) have been described where the structure is related to that of beta barrel pore-forming bacterial toxins and exhibits cellular toxicity. To investigate the relationship of Abeta APFs to disease and their ultrastructural localization in brain tissue, we conducted a pre-embedding immunoelectron microscopic study using anti-annular protofibril antiserum. We examined brain tissues of young- and old-aged amyloid precursor protein transgenic mice (APP23), neprilysin knockout APP23 mice, and nontransgenic littermates. alphaAPF-immunoreactions tended to be found (1) on plasma membranes and vesicles inside of cell processes, but not on amyloid fibrils, (2) with higher density due to aging, APP transgene, and neprilysin deficiency, and (3) with higher positive rate at synaptic compartments in aged APP23, especially in neprilysin knockout APP23 mice. These findings imply that APFs are distinct from amyloid fibrils, interact with biological membranes, and might be related to synaptic dysfunction in Alzheimer model mouse brains.

No MeSH data available.


Related in: MedlinePlus

Ultrastructural localization of annular protofibrils (APFs) in aged NEP+/+APP+  (a,c) and NEP−/−APP+ (b,d–f) mouse brain sections. DAB method. (a) Anti-annular protofibril immunoreactions (αAPF-IRs) on synaptic vesicles in axon terminal (AT) and vesicles in axon (Ax). Den: dendrite, Glia: glial process, and Mit: mitochondria. (b,c) αAPF-IRs on plasma membranes of dendrite (b) and unidentified process (UN) (c). (d) αAPF-IR on postsynaptic density (PSD). (e,f) αAPF-IRs were observed on plasma membranes and vesicles inside of cell processes (arrows) in senile plaques, but not on amyloid fibrils (Fib) and distended neurites (DN). Scale bar = 200 nm.
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fig2: Ultrastructural localization of annular protofibrils (APFs) in aged NEP+/+APP+ (a,c) and NEP−/−APP+ (b,d–f) mouse brain sections. DAB method. (a) Anti-annular protofibril immunoreactions (αAPF-IRs) on synaptic vesicles in axon terminal (AT) and vesicles in axon (Ax). Den: dendrite, Glia: glial process, and Mit: mitochondria. (b,c) αAPF-IRs on plasma membranes of dendrite (b) and unidentified process (UN) (c). (d) αAPF-IR on postsynaptic density (PSD). (e,f) αAPF-IRs were observed on plasma membranes and vesicles inside of cell processes (arrows) in senile plaques, but not on amyloid fibrils (Fib) and distended neurites (DN). Scale bar = 200 nm.

Mentions: Most of the αAPF-IRs were localized to cell processes in a patchy pattern in young Tg and aged mouse brains at the EM level. We did not measure the area of processes and cell bodies, and did not quantitatively compare the density of αAPF-IRs between processes and cell bodies. However, we found less apparent αAPF-IRs inside of cell bodies during observation by EM. Axons, dendrites, and small, unidentified processes showed αAPF-IRs (Figures 2(a), 2(b), and 2(c)). With regard to the unidentified processes, it is assumed that most were not glial but neuronal, due to their roundish appearance. Most of the αAPF-IRs were found on plasma membranes and vesicles inside of cell processes. In synapses, αAPF-IRs appeared on perisynaptic plasma membranes and synaptic vesicles (Figures 2(a), and 2(d)). αAPF-positive synapses exhibited a normal appearance. Although only a few immunoreactions were observed, postsynaptic densities also showed αAPF-IRs (Figure 2(d)). In aged NEP−/−APP+ and NEP+/+APP+ mouse brains in which many senile plaques appeared, αAPF-IRs were not found on amyloid fibrils or in distended neurites (Figures 2(e) and 2(f)).


Amyloid Beta annular protofibrils in cell processes and synapses accumulate with aging and Alzheimer-associated genetic modification.

Kokubo H, Kayed R, Glabe CG, Staufenbiel M, Saido TC, Iwata N, Yamaguchi H - Int J Alzheimers Dis (2009)

Ultrastructural localization of annular protofibrils (APFs) in aged NEP+/+APP+  (a,c) and NEP−/−APP+ (b,d–f) mouse brain sections. DAB method. (a) Anti-annular protofibril immunoreactions (αAPF-IRs) on synaptic vesicles in axon terminal (AT) and vesicles in axon (Ax). Den: dendrite, Glia: glial process, and Mit: mitochondria. (b,c) αAPF-IRs on plasma membranes of dendrite (b) and unidentified process (UN) (c). (d) αAPF-IR on postsynaptic density (PSD). (e,f) αAPF-IRs were observed on plasma membranes and vesicles inside of cell processes (arrows) in senile plaques, but not on amyloid fibrils (Fib) and distended neurites (DN). Scale bar = 200 nm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Ultrastructural localization of annular protofibrils (APFs) in aged NEP+/+APP+ (a,c) and NEP−/−APP+ (b,d–f) mouse brain sections. DAB method. (a) Anti-annular protofibril immunoreactions (αAPF-IRs) on synaptic vesicles in axon terminal (AT) and vesicles in axon (Ax). Den: dendrite, Glia: glial process, and Mit: mitochondria. (b,c) αAPF-IRs on plasma membranes of dendrite (b) and unidentified process (UN) (c). (d) αAPF-IR on postsynaptic density (PSD). (e,f) αAPF-IRs were observed on plasma membranes and vesicles inside of cell processes (arrows) in senile plaques, but not on amyloid fibrils (Fib) and distended neurites (DN). Scale bar = 200 nm.
Mentions: Most of the αAPF-IRs were localized to cell processes in a patchy pattern in young Tg and aged mouse brains at the EM level. We did not measure the area of processes and cell bodies, and did not quantitatively compare the density of αAPF-IRs between processes and cell bodies. However, we found less apparent αAPF-IRs inside of cell bodies during observation by EM. Axons, dendrites, and small, unidentified processes showed αAPF-IRs (Figures 2(a), 2(b), and 2(c)). With regard to the unidentified processes, it is assumed that most were not glial but neuronal, due to their roundish appearance. Most of the αAPF-IRs were found on plasma membranes and vesicles inside of cell processes. In synapses, αAPF-IRs appeared on perisynaptic plasma membranes and synaptic vesicles (Figures 2(a), and 2(d)). αAPF-positive synapses exhibited a normal appearance. Although only a few immunoreactions were observed, postsynaptic densities also showed αAPF-IRs (Figure 2(d)). In aged NEP−/−APP+ and NEP+/+APP+ mouse brains in which many senile plaques appeared, αAPF-IRs were not found on amyloid fibrils or in distended neurites (Figures 2(e) and 2(f)).

Bottom Line: Amyloid beta (Abeta) annular protofibrils (APFs) have been described where the structure is related to that of beta barrel pore-forming bacterial toxins and exhibits cellular toxicity.To investigate the relationship of Abeta APFs to disease and their ultrastructural localization in brain tissue, we conducted a pre-embedding immunoelectron microscopic study using anti-annular protofibril antiserum.We examined brain tissues of young- and old-aged amyloid precursor protein transgenic mice (APP23), neprilysin knockout APP23 mice, and nontransgenic littermates. alphaAPF-immunoreactions tended to be found (1) on plasma membranes and vesicles inside of cell processes, but not on amyloid fibrils, (2) with higher density due to aging, APP transgene, and neprilysin deficiency, and (3) with higher positive rate at synaptic compartments in aged APP23, especially in neprilysin knockout APP23 mice.

View Article: PubMed Central - PubMed

Affiliation: School of Health Sciences, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8514, Japan.

ABSTRACT
Amyloid beta (Abeta) annular protofibrils (APFs) have been described where the structure is related to that of beta barrel pore-forming bacterial toxins and exhibits cellular toxicity. To investigate the relationship of Abeta APFs to disease and their ultrastructural localization in brain tissue, we conducted a pre-embedding immunoelectron microscopic study using anti-annular protofibril antiserum. We examined brain tissues of young- and old-aged amyloid precursor protein transgenic mice (APP23), neprilysin knockout APP23 mice, and nontransgenic littermates. alphaAPF-immunoreactions tended to be found (1) on plasma membranes and vesicles inside of cell processes, but not on amyloid fibrils, (2) with higher density due to aging, APP transgene, and neprilysin deficiency, and (3) with higher positive rate at synaptic compartments in aged APP23, especially in neprilysin knockout APP23 mice. These findings imply that APFs are distinct from amyloid fibrils, interact with biological membranes, and might be related to synaptic dysfunction in Alzheimer model mouse brains.

No MeSH data available.


Related in: MedlinePlus