Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease

被引:54
作者
Mann, David M. A. [1 ]
Davidson, Yvonne S. [1 ]
Robinson, Andrew C. [1 ]
Allen, Nancy [1 ]
Hashimoto, Tadafumi [2 ]
Richardson, Anna [3 ]
Jones, Matthew [3 ]
Snowden, Julie S. [1 ,3 ]
Pendleton, Neil [1 ]
Potier, Marie-Claude [4 ]
Laquerriere, Annie [5 ,6 ]
Prasher, Vee [7 ]
Iwatsubo, Takeshi [2 ]
Strydom, Andre [8 ,9 ]
机构
[1] Univ Manchester, Salford Royal Hosp, Fac Biol Med & Hlth, Sch Biol Sci,Div Neurosci & Expt Psychol, Salford, Lancs, England
[2] Univ Tokyo, Grad Sch Med, Dept Neuropathol, Tokyo, Japan
[3] Salford Royal Hosp, Greater Manchester Neurosci Ctr, Cerebral Funct Unit, Stott Lane, Salford, Lancs, England
[4] UPMC, INSERM U1127, CNRS UMR7225, ICM Inst Cerveau & Moelle Epiniere,Hop Pitie Salp, 47 Bd Hop, Paris, France
[5] Rouen Univ Hosp, Dept Pathol, Rouen, France
[6] Normandie Univ, UNIROUEN, CHU Rouen, INSERM U1245, Team 4, F-76000 Rouen, France
[7] Birmingham Community NHS Trust, 30 Brookfield Rd, Birmingham B30 3QY, W Midlands, England
[8] Kings Coll London, Inst Psychiat Psychol & Neurosci, 16 Crespigny Pk, London, England
[9] UCL, Div Psychiat, 147 Tottenham Court Rd, London, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
Alzheimer's disease; Down syndrome; APP mutations; Cerebral amyloid angiopathy; Amyloid plaques; A-BETA-DEPOSITION; LOCUS DUPLICATION; NEUROPATHOLOGIC ASSESSMENT; FRONTOTEMPORAL DEMENTIA; CEREBRAL-HEMORRHAGE; NATIONAL INSTITUTE; SENILE PLAQUES; ANGIOPATHY; PROTEIN; A-BETA-42(43);
D O I
10.1007/s00401-018-1866-3
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE epsilon 4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE epsilon 4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of A beta, with higher levels of A beta(40) promoting a more 'aggressive' form of CAA, and higher levels of A beta(42(3)) favouring a greater plaque burden. Possession of APOE epsilon 4 allele, especially epsilon 4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD.
引用
收藏
页码:569 / 587
页数:19
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