Elsevier

Neurobiology of Aging

Volume 33, Issue 5, May 2012, Pages 1010.e1-1010.e13
Neurobiology of Aging

Abstracts of online article
The Arctic amyloid-β precursor protein (AβPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aβ

https://doi.org/10.1016/j.neurobiolaging.2011.10.022Get rights and content

Abstract

The Arctic (p. E693G) mutation in the amyloid-β precursor protein (AβPP) facilitates amyloid-β (Aβ) protofibril formation and generates clinical symptoms of Alzheimer's disease (AD). Here, molecular details of Aβ in post mortem brain were investigated with biochemical and morphological techniques. The basic structure of Arctic plaques resembled cotton wool plaques. However, they appeared ring-formed with Aβ42-specific antibodies, but were actually targetoid, since the periphery and center of many parenchymal Aβ deposits stained differently with mid-domain, N- and C-terminal Aβ antibodies. Aβ fibrils were similar in shape, albeit shorter than in sporadic AD brain, when examined by electron microscopy. Aβwild-type and Aβarctic codeposited and parenchymal deposits were highly enriched in both N- and C-terminally truncated Aβ. In contrast, cerebral amyloid angiopathy (CAA) contained a substantial amount of Aβ1-40. The absence of plaques with cores of fibrillary Aβ might be due to the scarcity of full-length Aβ, although other mechanisms could be involved. Our findings are discussed in relation to mechanisms and relevance of amyloid formation and to the clinical features of AD.

Introduction

Various parenchymal amyloid-β (Aβ) deposits, as well as cerebral amyloid angiopathy (CAA) in vessel walls, are typically found in the Alzheimer's disease (AD) brain. The identification of autosomal dominant forms of early-onset AD proved that the polymerization and accumulation of Aβ can be pathogenic (Hardy and Selkoe, 2002). The plaques can be composed either of densely packed Aβ aggregates with an amyloid core and a neuritic corona or describe more diffusely arranged deposits. Whereas some studies suggest that disease severity in sporadic AD relates to the extent of neuritic plaques, the clinicopathological correlation seems to be more evident with the total levels of Aβ, neurofibrillary pathology or synaptic loss (Ingelsson et al., 2004, Näslund et al., 2000, Nelson et al., 2009). The Aβ precursor protein (AβPP) is cleaved by β- and γ-secretase to generate aggregation-prone Aβ species. The diversity is further enhanced by post-translational modifications, e.g., truncation and isomerization as well as cyclization which leads to the formation of pyroglutamate modified (pE) Aβ (Roher et al., 1993, Saido et al., 1995). Extracts of Aβ from the AD post mortem brain are therefore highly heterogeneous and complex. Cases with monogenetic disease forms enable us to study the pathological and clinical effect of a single genetic lesion and extrapolate the observations to the vast majority of sporadic disease forms. For example, the Aβ isoform pattern does not differ much between sporadic and familial AD when analyzed with mass spectrometry, underscoring notable similarities between familial AD and sporadic disease (Portelius et al., 2010). However, quantitative analyses have often shown that Aβ42-but not Aβ40-immunoreactive plaque burden is increased in familial AD as compared to sporadic AD (Shepherd et al., 2009). Some unique types of deposits, such as cotton wool plaques (CWPs) and inflammatory plaques have been described in brains of presenilin-1 (PS-1) mutation carriers (Crook et al., 1998, Shepherd et al., 2005). Moreover, cerbrovascular Aβ deposits are usually more frequent in familial AD, particularly when the mutation is located in PS-1 or inside the Aβ domain of the AβPP. Duyckaerts and colleagues have recently provided an excellent review on the nomenclature and classification of Aβ deposits in AD brain (Duyckaerts et al., 2009).

Genetic lesions, close to the α-secretase cleavage site in the AβPP gene, like the Flemish [p. A692G, (Hendriks et al., 1992)], Dutch [p.E693Q, (Levy et al., 1990)], Italian [p.E693K, (Tagliavini et al., 1999)] and Iowa mutation [p.D694N (Grabowski et al., 2001)] often result in fatal cerebral hemorrhages, although patients with less severe symptoms develop dementia. In contrast, the Arctic mutation [p. E693G] leads to early-onset AD with no signs of cerebrovascular events (Basun et al., 2008, Nilsberth et al., 2001). This mutation results in increased formation of Aβ protofibrils, i.e., large soluble Aβ aggregates, in vitro (Johansson et al., 2006, Nilsberth et al., 2001) and in vivo (Englund et al., 2007). Similarly a recessive mutation in the AβPP gene, the Osaka mutation (p. E693Δ), results in an AD-type dementia and enhanced Aβ oligomerization (Tomiyama et al., 2008), possibly suggesting that enhanced Aβ protofibril/oligomer formation is a general pathogenic mechanism of AD. The neuropathology associated with the Arctic AβPP mutation has previously been briefly described (Basun et al., 2008). Here, fresh frozen and formalin-fixed brain tissues from 2 autopsied cases were used to perform biochemical analyses of Aβ deposits. A more comprehensive morphological analysis of AD neuropathology will be described in a separate report.

Section snippets

Brain tissues

Brain tissues from 2 patients with the Arctic AβPP mutation [subjects IV: 10 and IV: 29 (Basun et al., 2008)] were obtained from the Huddinge and Uppsala Brain Banks respectively. Four cases with a mutation in presenilin 1 [PS1Δ9, subjects III: 7, III: 15, III: 18 and III: 21 (Verkkoniemi et al., 2001)] and 6 sporadic AD cases were also investigated. The material was provided by Helsinki University brain bank. The sporadic AD cases were diagnosed as CERAD C and Braak Stage V/VI (Table 1).

Histopathological analyses

Anti-Aβ antibodies specific for the N-, mid-domain and C-terminus depict Aβ plaques differently

The parenchymal Aβ plaques in patients with the Arctic AβPP mutation were abundant, occupying an area fraction of ∼25% in the gray matter of temporal cortex (quantified in layer I–VI, Brodmann area 21). They were large, readily detectable with H&E (Suppl Fig. 1A), associated with weak neuritic, microglial and astrocytic response, devoid of congophilic amyloid cores, i.e., they resembled cotton wool plaques (Crook et al., 1998). However immunostaining of Arctic plaques and cotton wool plaques

Discussion

Ring-formed parenchymal plaques were found in brains of patients with the Arctic AβPP mutation when stained with a C-terminal Aβ42-specific antibody or silver impregnation techniques (Basun et al., 2008). Here we examined these neuropathological lesions in greater detail. The center of some plaques was immunoreactive with N-terminal Aβ antibodies, but the majority of plaques were immunopositive with mid-domain and Aβ40-specific antibodies. The results suggest that Aβ in the interior is usually

Disclosure statement

There are no actual or potential conflicts of interest in this study. Appropriate procedures have been pursued according to guidelines for ethical conduct in science and the study has been approved by the Regional ethical committee in Uppsala (2009)/089; 2009–04–22 and 2005–103; 2005–2006–29.

Acknowledgements

This work was funded by grants from Uppsala University, Landstinget in Uppsala län, the Swedish Research Council [#2009–4567) L.L., (#2009–4389) LN, (#2006–6326; #2006–3464) M.I. and (#2008–2957) Bengt Winblad], the Swedish Brain Foundation, Bertil Hållstens Forskningsstiftelse, Alzheimer-fonden (L.L.), Gamla Tjänarinnor, Gun och Bertil Stohnes Stiftelse (LN, O.P.), Magnus Bergvall, Åhlénsstiftelsen, Lars Hierta, Lundströms Minne, Frimurarstiftelsen, Svenska Läkarsällskapet (LN, M.I.), Helsinki

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