Characterization of amyloid β protein species in cerebral amyloid angiopathy of a squirrel monkey by immunocytochemistry and enzyme-linked immunosorbent assay

Perivascular spaces (PVS) are fluid-filled spaces surrounding cerebral blood vessels. MRI-visible, supposedly enlarged, PVS in the centrum semiovale (CSO) have been associated with cerebral amyloid angiopathy (CAA). PVS enlargement may be due to perivascular clearance impairments, potentially caused by increased amyloid-β (Aβ) accumulation in the walls of vessels in the overlying cortex. We test this hypothesis, using MRI-guided histopathological examination of PVS in CAA autopsy cases. The cohort included 19 CAA (74.1±8.2y, 7F) and 5 non-CAA control cases (88.0±4.9y, 3F). Formalin-fixed hemispheres were scanned on a 3T MRI scanner, including a 500μm T2-weighted sequence. PVS enlargement was assessed in the CSO on in vivo and ex vivo MRI. In addition, local score of PVS enlargement was assessed in four pre-defined juxtacortical areas (Fig.A), using a semiquantitative score and on the corresponding histological sections (Fig.B). Severity of leptomeningeal and cortical CAA were assessed on adjacent Aβ-stained sections, using a semiquantitative scale.PVS enlargement was more severe in CAA cases compared to controls, both on in vivo and ex vivo MRI (p<0.05). PVS enlargement on ex vivo MRI positively correlated with the severity of PVS enlargement on the corresponding histopathological samples (Fig.C). Within CAA cases, the degree of PVS enlargement on ex vivo MRI was positively associated with leptomeningeal CAA severity (n=52 samples, ρ=0.35, p=0.011), but not cortical CAA severity (n=52 samples, ρ=0.10, p=0.472). These preliminary findings confirm that the degree of MRI-visible PVS in juxtacortical brain areas reflects enlargement on histopathology. Moreover, they suggest that PVS enlargement in cases with CAA corresponds to increased CAA severity in the overlying leptomeningeal vessels, possibly as a result of impaired perivascular clearance. Future directions include characterization of individual blood vessels associated with PVS enlargement.

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Cerebral amyloid angiopathy and comparative analysis of amyloid-β protein in birds

10.1101/486340 ◽

2018 ◽

Author(s):

Yumi Une ◽

Mutsumi Yamazaki ◽

Maho Morimoto ◽

Fuyuki Kametani ◽

Dennilyn Parker ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Sequence ◽

Cerebral Amyloid Angiopathy ◽

Senile Plaques ◽

Neurofibrillary Tangle ◽

Bird Species ◽

Amyloid Β ◽

Amyloid Angiopathy ◽

Amyloid Β Protein ◽

Cerebral Amyloid

Senile plaques and cerebral amyloid angiopathy (CAA)?are well-documented in various mammals, and several species even exhibit neurofibrillary tangle (NFT). However, we know far less about whether such symptoms are present in birds. Therefore, here we clarified the occurrence and pathogenesis of avian aβ-related lesions, analyzing the aβ amino-acid sequence across 28 birds at multiple life stages, representing 15 species, 14 genera, and 9 nine families.?We also determined the expected aβ amino-acid sequence after comparing data from the brains of nine birds (seven species) with publicly available NCBI data. We observed CAA and senile plaque-like deposition only in a female Amazon parrot, estimated to be around 30–40 years old. We identified two Aβ depositions (40 and 42) in the same location that correspond to Aβ 6-42. Additionally, we observed severe Aβ deposition, accompanied by severe hemorrhaging, in blood vessels of the superficial and deep portions of the brain. These lesions were directly related to the cause of death. Of 40 bird species, 36 exhibited type 1 Aβ amino-acid sequences, similar to humans. Given that all of these birds were old, our results suggest that Aβ is deposited primarily as CAA as the animals age. This report is the first clinically based description of CAA in birds. Interspecific variation likely exists because we identified species that did not exhibit Aβ deposition even when the birds are old enough. However, even birds of the same taxonomic status differed in whether they possessed or lacked Aβ deposition. Thus, other factors besides Aβ amino-acid sequence could influence this symptom.

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