amyloid β protein (aβ) deposition in dementia with lewy bodies: predominance of aβ42(43) and...

Neuropathology and Applied Neurobiology (1998), 24, 187–194

Amyloid b protein (Ab) deposition in dementia withLewy bodies: predominance of Ab

42(43)and paucity of

Ab40

compared with sporadic Alzheimer’s diseaseD. M. A. Mann*, S. M. Pickering Brown†, F. Owen†, M. Baba‡ and T. Iwatsubo‡

*Department of Pathological Sciences, Division of Molecular Pathology, †School of Biological Sciences, Division of NeuroscienceUniversity of Manchester, Manchester, UK and ‡Department of Neuroscience and Neuropathology, University of Tokyo, Japan

D. M. A. Mann, S. M. Pickering Brown, F. Owen, M. Baba and T. Iwatsubo (1998) Neuropathology and AppliedNeurobiology 24, 187–194Amyloid b protein (Ab) deposition in dementia with Lewy bodies: predominance of Ab

42(43)and

paucity of Ab40

compared with sporadic Alzheimer’s disease

Amyloid b protein (Ab) deposition was investigated by viewpoint that in all disorders in which Ab deposition ischaracteristic, the initial and predominant peptide speciesquantitative immunohistochemistry in 13 cases of

dementia with Lewy bodies (DLB) and compared with deposited is the longer form, Ab42(43)

. The density ofLewy bodies (LB) in DLB was unrelated to the extent ofthat in a series of age, gender and ApoE genotype

matched cases of Alzheimer’s disease (AD). In DLB the Ab deposition, although those cases possessing one ormore copies of the apolipoprotein E E4 allele had apredominant Ab peptide species deposited was Ab

42(43)and this was similar in amount to that in AD. By higher LB density than those without an E4 allele. This

suggests that the apolipoprotein E E4 isoform mightcontrast, Ab40

deposition was sparse in DLB and waslower than that in AD as was the total Ab facilitate, though not necessarily trigger, the formation

of LB in susceptible individuals.(Ab40+Ab

42(43)) deposition. These data reinforce the

Keywords: amyloid b protein, dementia with Lewy bodies, Alzheimer’s disease, Lewy bodies, immunohistochemistry

Ab42(43)

with diCering carboxy-terminal residues accord-Introduction

ing to the exact site of c secretase cleavage [43]. Thesetwo Ab species are not uniformly distributed throughAlzheimer’s disease (AD) is associated neuropatholog-

ically with a widespread deposition of amyloid b protein the brain. Ab42(43)

is the predominant peptide speciesdeposited and is present in many cerebral cortical regions(Ab) throughout the cerebral cortex in the morphological

form of diCuse and cored plaques. Additionally, numer- and in the basal ganglia and cerebellum in plaques ofall morphological types [7,15,22,24,26,14–16,ous nerve cells containing neurofibrillary tangles (NFT)

are present throughout the association neocortex, hippo- 30,35,37,18–20,42]. Ab40

however, is more restrictedin its topographic distribution being essentially confinedcampus and amygdala. Ab is the enzyme (b and c

secretase) mediated catabolic product of its precursor, to the cored plaques of the cerebral cortex[7,15,22,26,28,14–16,35,37,18–20,42] and cerebel-APP, and is present in the brain as a 39–43 amino acid

peptide [23,38 for reviews]. The Ab within plaques is lum [24,29], being virtually absent from the diCuseplaques of both these regions.composed mostly of two molecular variants, Ab

40and

Dementia with Lewy bodies (DLB), also known ascortical Lewy body disease [25], diCuse Lewy body

Correspondence: Dr D. M. A. Mann, Department of Pathologicaldisease [6], Lewy body variant of AD [12] or senileSciences, Division of Molecular Pathology, University of Manchester,

Oxford Road, Manchester M13 9PT, UK. dementia of Lewy (body) type [11,33,36] shares many

187© 1998 Blackwell Science Ltd

188 D. M. A. Mann et al.

of the histopathological characteristics of AD. Besides Ab42(43)

, with that present in cases of AD matched forgender and age at onset of disease. Furthermore, becausethe numerous cortical and subcortical Lewy bodies (LB),

most cases show a widespread deposition of Ab, mainly the amount of Ab deposited, and particularly of Ab40

[9,31], is dependent upon apolipoprotein E (APOE) geno-as diCuse plaques, throughout the cerebral cortex, cer-ebellum and striatum although cored plaques are not so type, DLB and AD cases were also matched in this respect.frequent and may sometimes be completely absent.Neurofibrillary tangles are usually sparse, and are most

Materials and methodsoften confined to the hippocampal formation, althoughin some instances these can be as widespread throughout Brains were available from 13 consecutive cases of

clinically diagnosed [4] and pathologically verifiedthe neocortex as is seen in AD [6,12,13,25,36].Although Ab deposition is commonplace in DLB, the [6,12,36] DLB, ranging from 60 to 84 years of age at

onset and 62 to 88 years of age at death, accessedmolecular form in which this peptide is deposited isuncertain, and it is not clear how the total amount of during the period 1992–96 (Table 1).

Tissues were also drawn from our archive for 13 casesAb deposited in this disorder compares with that of AD.In the present study we have compared the total amount of sporadic AD, matching the DLB cases for gender, age

at onset of disease and APOE genotype (Table 1). APOEof Ab deposited in DLB, and separately as Ab40

and

Table 1. Clinical and pathological details of 13 cases of DLB and 13 of AD

Case Gender Onset Age at Duration Brain APOEage (y) death (y) (y) weight (g) genotype

Dementia with Lewy bodies (DLB)1 M 60 63 3 1370 3,42 M 60 72 12 1350 3,43 M 61 66 5 1320 4,44 M 61 62 1 1310 3,35 F 62 70 8 1340 3,46 M 65 74 9 1416 3,47 F 67 71 4 1110 4,48 M 70 73 3 1385 3,39 F 72 84 12 981 3,4

10 M 77 79 2 1400 4,411 F 81 85 4 1175 2,312 M 82 88 6 1137 3,413 F 84 85 1 1094 4,4Mean±sd – 69.4±9.0 74.7±8.7 5.4±3.8 1260±142 –

Alzheimer’s disease (AD)1 M 60 68 8 1035 3,42 M 60 65 5 1370 3,43 M 64 68 4 1250 4.44 M 62 71 9 1245 3.35 F 63 76 13 950 3,46 M 65 71 6 1210 3.47 F 68 76 8 1150 4,48 M 70 78 8 1297 3,39 F 70 77 7 1020 3,4

10 M 73 77 4 1398 4,411 F 80 86 6 1400 2,312 M 84 87 3 1242 3,413 F 82 88 6 1075 4,4– – 69.3±8.3 76.0±7.5 6.7±2.6 1203±148 –

© 1998 Blackwell Science Ltd, Neuropathology and Applied Neurobiology, 24, 187–194

Amyloid deposition in dementia with Lewy bodies 189

genotyping were performed, using frozen brain tissue, but only a subset of plaques, which were of the cored,rather than diCuse, variety.according to method of Wenham et al. [41].

The brains had been fixed by immersion in 10% In AD, Ab42(43)

immunoreactive plaques were presentthroughout all layers of the frontal cortex; they wereneutral formalin for 3–4 weeks, from which blocks of

frontal cortex (Brodman areas 8,9) were cut and rou- numerous as diCuse deposits within the outer corticallaminae (layer II and upper layer III) (Figure 1b). Theretinely processed into paraBn wax. Serial sections were

cut at a thickness of 6 mm and immunostained using was little apparent variation between the number ofsuch deposits from case to case. By contrast, plaquesend specific monoclonal antibodies BC05 and BA27 [15]

to detect plaques and blood vessel walls containing containing Aß40 were always less common than plaquescontaining Ab

42(43)ones and were more often locatedAb

42(43)(BC05) and Ab

40(BA27), respectively.

Immunostained sections were subjected to computerized within the deeper cortical laminae (Figure 1d). Thenumber of Ab

40plaques was much more variable, withmorphometry as previously described [15]. The numeri-

cal density and the proportion of the area occupied by some cases of AD containing many such plaques butothers relatively few.Ab

42(43)and Ab

40containing plaques was determined,

as was the ratio between these measures (Ab405Ab

42(43)) In DLB, plaques were present in every instance except

one (case 8). Ab42(43)

containing plaques were againboth in terms of plaque density (number per mm2) andarea proportion (% of tissue occupied). The Ab load data more numerous than Ab

40plaques and were distributed

in a similar way to those in AD (Figure 1a). Ab40

plaquesin DLB cases was compared to that in AD using theMann–Whitney U-test. were, however, sparse (or absent) (Figure 1c) in all

except cases 1, 3 and 11 where, although the densityAdjacent sections of frontal cortex, and other sectionsof hippocampus and entorhinal cortex, were stained for was higher than in the other DLB cases, this was only

similar to that seen in those cases of AD with the fewestNFT using a sensitive silver technique (Palmgren’smethod [5]) and by tau immunostaining using tau-2 Ab

40plaques. Nonetheless, when present, Ab

40plaques

in DLB were distributed in a manner not obviouslyantibody (Sigma Chemical Company) at a dilution1/750. diCerent to that in AD.

The numerical density of Ab42(43)

plaques in DLBOther adjacent serial sections were immunostained forubiquitin (to detect Lewy bodies) using the mouse mono- (when present) was not significantly diCerent from that

in AD, although the density of Ab40

plaques was muchclonal antibody 1510 (Chemicon) at a dilution of 1/500[17]. The density of nerve cells containing LB was lower (P<0.001), as was the ratio between the density

of Ab40

and Ab42(43)

plaques (P<0.001) (Table 2). Theestimated by direct counting under the microscope usingan eyepiece graticule at a magnification of ×20, equival- Ab load, as Ab

42(43), was slightly lower in DLB (but not

significantly so) although the Ab40

load (P<0.001) andent to a field size of 1.26 mm2 ; counts per field wereconverted into number per mm2 . The density of LB the total (Ab

40and Ab

42(43)) Ab load (P<0.001) and

the ratio between Ab40

and Ab42(43)

loads (P<0.001)within DLB cases bearing one or more ApoE E4 alleleswas compared with those cases without an E4 allele were all significantly lower in DLB.again by Mann–Whitney U-test, and was also correlatedto measures of Ab deposition and NFT score using the

Neurofibrillary tanglesSpearman rank correlation statistic.

NFT were (by definition) numerous in all cases of AD inwhich extracellular and intracellular tangles were wide-

Resultsspread within layer II of the entorhinal cortex CA1 andsubiculum of the hippocampus and layers III and V of

Amyloid (Ab) depositionthe frontal cortex. In DLB, NFT were much more variable;they were absent from the entorhinal cortex in one case,In all 26 cases, the monoclonal antibody BC05, detecting

Ab42(43)

, stained all Ab containing plaques and blood from the hippocampus in three cases and from theneocortex in four. As in AD, NFT were typically numer-vessels in a manner equivalent to that previously

described [15]. By contrast, the monoclonal antibody ous in entorhinal cortex layer II, in most cases of DLB,although moderate in number or numerous in area CA1BA27 [15] stained all (Ab

40containing) blood vessels



a

c d

b



Table 2. Measures of Ab deposition and Lewy body density in DLB and AD

Case Plaque density % Ratio Amyloid load (% area) % Ratio Lewy(n/mm2) Ab

40:Ab

40:bodies

Ab42(43)

Ab42(43)

Ab40

Ab40+ Ab

42(43)(n/mm2)

Ab42(43)

Ab40

Ab42(43)

Dementia with Lewy bodies (DLB)1 173 16.1 9.3 8.5 1.33 9.8 15.6 10.52 288 0.4 0.1 3.9 0.04 3.9 1.0 10.93 124 38.4 31.0 6.2 0.76 6.9 12.3 21.14 729 4.2 0.6 6.8 0.08 6.9 1.2 4.45 164 1.9 1.2 5.4 0.07 5.5 1.3 11.96 205 3.3 1.6 4.2 0.06 4.3 1.5 12.67 158 5.2 3.3 4.9 0.25 5.1 5.1 6.68 0 0.0 0.0 0.0 0.0 0.0 0.0 11.29 315 3.8 1.2 8.5 0.26 8.8 3.1 10.2

10 194 6.1 3.1 4.9 0.51 5.4 10.3 8.211 308 14.0 4.5 6.3 0.68 6.9 10.9 4.412 84 4.8 5.7 1.9 0.17 2.0 9.1 7.513 40 5.2 13.1 1.4 0.10 1.5 7.4 5.4Mean*±sd 232±178 8.6±10.4 6.2±8.7 5.2±2.3 0.36±0.39 5.6±2.5 6.6±5.1 9.5±4.6

Alzheimer’s disease (AD)1 153 80 52.3 6.0 5.4 11.4 90.0 —2 253 109 43.1 7.8 2.6 10.4 33.3 —3 259 158 61.0 8.0 10.9 18.9 136.3 —4 242 8 3.3 10.1 0.4 10.5 4.0 —5 274 20 7.2 7.7 1.4 9.1 18.2 —6 252 14 5.6 6.1 1.1 7.2 18.0 —7 107 41 38.3 6.1 2.9 9.0 47.5 —8 111 68 61.3 8.3 0.1 9.4 1.7 —9 455 239 52.5 9.5 8.4 17.9 88.4 —

10 166 34 20.5 6.2 2.2 8.4 35.5 —11 276 19 6.9 5.7 0.4 6.1 7.0 —12 347 218 62.8 11.7 7.1 18.8 60.7 —13 87 18 20.7 4.4 1.5 5.9 34.1 —Mean*±sd 239±102 79.9±102 31.2±23.0 7.4±2.1 3.7±3.5 11.1±4.8 47.8±39.7

*Mean value excludes data from case 8 in both AD and DLB, except for Lewy body density measures.

of hippocampus, and only rare (or absent) in the neocor-Lewy bodies

tex; in two instances, however, NFT were moderatelycommon in the frontal cortex (Table 3). These rating Again by definition, LB were absent from the frontal

cortex in AD. In DLB the density of Lewy bodies variedvalues were pooled to give an overall NFT score (Table 3).This NFT score correlated significantly with total Ab widely (Table 2) but this did not correlate with any

measure of Ab deposition or NFT score.load (rs=0.774; P<0.01), Ab

42(43)load (r

s=0.696;

P<0.02) and Ab40

load (rs=0.657; P<0.05) but not The mean density of LB was higher (P<0.05) in the

10 patients bearing an E4 allele, than in those threewith Ab40

or Ab42(43)

plaque density measures.

Figure 1. Amyloid b protein (Ab) deposition in a 66-year-old male with DLB and ApoE genotype E4, E4 (patient 3) (a,c) and in an age,gender and ApoE matched patient with AD (b,d). Note similar levels of Ab

42(43)immunoreaction in DLB (a) and AD (b), whereas in DLB (c)

the level of Ab40

immunoreaction is much lower than that in AD (d). Immunoperoxidase-haematoxylin. ×125.



Table 3. NFT rating in neocortex, entorhinal cortex and hippocampus in DLB and AD

Dementia with Lewy bodies (DLB) Alzheimer’s disease (AD)

Case Neocortex Entorhinal Hippocampus NFT score Case Neocortex Entorhinal Hippocampus NFT scorecortex cortex

1 ++ +++ +++ 8 1 +++ +++ +++ 92 + + + 3 2 +++ +++ +++ 93 + +++ +++ 7 3 +++ +++ +++ 94 + ++ + 4 4 +++ +++ +++ 95 + +++ ++ 6 5 +++ +++ +++ 96 + +++ ++ 6 6 +++ +++ +++ 97 ++ +++ +++ 8 7 +++ +++ +++ 98 0 + 0 1 8 +++ +++ +++ 99 + +++ ++ 6 9 +++ +++ +++ 9

10 0 +++ ++ 5 10 +++ +++ +++ 911 ++ +++ ++ 7 11 +++ +++ +++ 912 0 + 0 1 12 +++ +++ +++ 913 0 0 0 0 13 +++ +++ +++ 9

patients without; there were no diCerences between the may have obscured real diCerences in total Ab since itis known in AD at least that the E4 allele is preferentiallyfour E4 homozygotes or the six E4 heterozygotes in this

respect (no E4, 6.7±3.9; one E4, 10.6±1.8; two E4, associated with a heavier Ab40 deposition [9,31].Imbalances in E4 allele bearers between AD and DLB10.3±7.3).groups (in favour of DLB) may thus have disproportion-ately and artifactually elevated Ab

40(and total load) in

Other diVerencesthis latter group in other studies [1,11,33].

Present data add to the growing wealth of informationThe mean brain weight was slightly lower (5%) in ADcompared with DLB (Table 1). Duration of illness was drawn from patients with familial AD [20,27,28,30],

sporadic AD [15,18,22,35,37,42], Down’s syndromeshorter (by 1.3 years) in DLB than in cases of AD withsimilar onset age (Table 1), although neither of these [14,16,18, 19], normally aged individuals [7] and most

recently, head injured individuals [10] showing that, indiCerences reached statistical significance.all these instances in which Ab plaques are to be found,Ab

42(43)is the predominant peptide species present.

DiscussionIndeed, in the case of early Down’s syndrome [14,16,18,19], and in most younger head injured individuals [10],The main finding in this study is that in DLB Ab

42(43)is

the predominant Ab species deposited in the brain with Ab42(43)

is the sole peptide species present. Such datahave led to the concept that plaque formation is initiatedAb

40being a minor component of plaques. When com-

pared with age, gender and APOE genotype-matched by a deposition of Ab42(43)

; this event is perhaps dictatedby the local concentration of soluble Ab

42(43)within thecases of sporadic AD, Ab

42levels were similar although

the Ab40

content and total Ab(Ab40+Ab

42(43)) levels extracellular space [39,40] with deposition occurring

once a critical threshold concentration has beenwere very much lower. Previous studies [1,11,33] havedetected no diCerence in total Ab (either as plaque exceeded.

The position of DLB with regard to the pathologicaldensity or amyloid load) in temporal cortex and hippo-campus between AD and DLB cases, but although AD deposition of Ab is highly reminiscent of that seen in

Down’s syndrome individuals aged between 40 andand DLB cases were of similar age range no attempt wasmade in these studies to control for APOE genotype. It 50 years in whom Ab

42(43)levels are high and Ab

40levels low [14,20]. Indeed, there are further parallels inis therefore possible that diCerences in APOE E4 allele

frequency in AD and DLB groups in these latter studies the extent and distribution of NFT formation, which are



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27 Mann DMA, Iwatsubo T, Ihara Y et al. Predominant Biochem Biophys Res Commun 1994; 200: 1598–60340 Teller JK, Russo C, de Busk LM et al. Presence of solubledeposition of Ab42 (43) in plaques in cases of Alzheimer’s

disease and hereditary cerebral haemorrhage associated amyloid b peptide precedes amyloid plaque formation inDown’s syndrome. Nature Med 1996; 2: 93–5with mutations in the amyloid precursor protein gene. Am

J Pathol 1996; 148: 1257–66 41 Wenham PR, Price WH, Blundell C. Apolipoprotein Egenotyping by one-stage PCR. Lancet 1991; 337: 1158–928 Mann DMA, Iwatsubo T, Cairns NJ et al. Amyloid (Ab)

deposition in chromosome 14-linked Alzheimer’s disease: 42 Yamaguchi H, Sugiahra S, Ishiguro K, Takashima A, HiraiS. Immunohistochemical analysis of COOH-termini of amyl-predominance of Ab

42 (43).Ann Neurol 1996; 40: 149–56

29 Mann DMA, Iwatsubo T, Snowden JS. Atypical amyloid oid beta protein (Ab) using end-specific antisera for Ab40and Ab42 in Alzheimer’s disease and normal aging.(Ab) deposition in the cerebellum in Alzheimer’s disease:

an immunohistochemical study using end-specific Ab mon- Amyloid: Int J Clin Invest 1995; 2: 7–16oclonal antibodies. Acta Neuropathol 1996; 91: 647–53

30 Mann DMA, Iwatsubo T, Nochlin D, Sumi SM, Levy-Lahad Received 24 October 1997E, Bird TD. Amyloid (Ab) protein deposition in chromosome

Accepted after revision 3 February 19981 linked Alzheimer’s disease – the Volga German kindreds.Ann Neurol 1997; 41: 52–7


amyloid β protein (aβ) deposition in dementia with lewy bodies: predominance of aβ42(43) and...

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