Abstracts of online articleThe Arctic amyloid-β precursor protein (AβPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aβ
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
References (55)
- et al.
Chemical characterization of Abeta 17–42 peptide, a component of diffuse amyloid deposits of Alzheimer disease
J. Biol. Chem
(1994) - et al.
High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain
Neuroscience
(2006) - et al.
Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain
Biochem. Biophys. Res. Commun
(2000) - et al.
Development of Abeta terminal end-specific antibodies and sensitive ELISA for Abeta variant
Biochem. Biophys. Res. Commun
(2004) - et al.
Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores
J. Mol. Biol
(2003) - et al.
Secretion and intracellular generation of truncated Abeta in beta-site amyloid-beta precursor protein-cleaving enzyme expressing human neurons
J. Biol. Chem
(2003) - et al.
The Arctic Alzheimer mutation facilitates early intraneuronal Abeta aggregation and senile plaque formation in transgenic mice
Neurobiol. Aging
(2006) - et al.
Observations in APP bitransgenic mice suggest that diffuse and compact plaques form via independent processes in Alzheimer's disease
Am. J. Pathol.
(2011) - et al.
Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer's disease
Arch. Biochem. Biophys
(1993) - et al.
A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice
Neurobiol. Aging
(2009)