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Table S3. Proteins identified in supernatant with decreased expression in the presubiculum compared to the entorhinal cortex in Alzheimer’s disease post-mortem brain tissue. (DOCX 24 kb)

Table S2. Proteins identified in the pellet with increased expression in the presubiculum compared to the entorhinal cortex in Alzheimer’s disease post-mortem brain tissue. (DOCX 38 kb)

Table S4. Proteins identified in the pellet with decreased expression in the presubiculum compared to the entorhinal cortex in Alzheimer’s disease post-mortem brain tissue. (DOCX 86 kb)

Table S5. Webgestalt GO ontology terms showing increased expression in the presubiculum compared to the entorhinal cortex in Alzheimer’s disease post-mortem brain tissue. (DOCX 18 kb)

Table S1. Proteins identified in supernatant with increased expression in the presubiculum compared to the entorhinal cortex in Alzheimer’s disease post-mortem brain tissue. (DOCX 24 kb)

Table S6. Webgestalt GO ontology terms showing decreased expression in the presubiculum compared to the entorhinal cortex in Alzheimer’s disease post-mortem brain tissue. (DOCX 18 kb)

Background The deposition of neurotoxic amyloid-β (Aβ) peptides in plaques in the brain parenchyma and in cerebral blood vessels is considered to be a key event in Alzheimer’s disease (AD) pathogenesis. Although the presence and impact of full-length Aβ peptides such as Aβ1–40 and Aβ1–42 have been analyzed extensively, the deposition of N-terminally truncated Aβ peptide species has received much less attention, largely because of the lack of specific antibodies. Methods This paper describes the generation and characterization of novel antibodies selective for Aβ4–x peptides and provides immunohistochemical evidence of Aβ4–x in the human brain and its distribution in the APP/PS1KI and 5XFAD transgenic mouse models. Results The Aβ4–x staining pattern was restricted mainly to amyloid plaque cores and cerebral amyloid angiopathy in AD and Down syndrome cases and in both AD mouse models. In contrast, diffuse amyloid deposits were largely negative for Aβ4–x immunoreactivity. No overt intraneuronal staining was observed. Conclusions The findings of this study are consistent with previous reports demonstrating a high aggregation propensity of Aβ4–x peptides and suggest an important role of these N-truncated Aβ species in the process of amyloidogenesis and plaque core formation.

Quantification of extracellular 029-1 positive plaque load in cortex, subiculum, and thalamus in heterozygous and homozygous 9-month-old 5XFAD mice. (PDF 119 kb)

CIEF electropherograms for antibodies 6E10 and 029-1. (PDF 184 kb)

Predominant plaque core staining using 029-2 in a patient with sporadic AD. (PDF 183 kb)

Cerebral amyloid angiopathy （CAA） is increasingly recognized as a major contributor of Alzheimer’s disease（ AD） pathogenesis. To date, vascular deposits and not parenchymal plaques appear more sensitive predictors of dementia. Amyloid deposition in and around cerebral blood vessels plays a central role in a series of response mechanisms that lead to changes in the integrity of the blood-brain barrier, extravasations of plasma proteins, edema formation, release of inflammatory mediators and matrix metalloproteases which, in turn, produce partial degradation of the basal lamina with the potential to develop hemorrhagic complications. The progressive buildup of amyloid deposits in and around blood vessels chronically limits blood supply and causes focal deprivation of oxygen, triggering a secondary cascade of metabolic events several of which involve the generation of nitrogen and oxygen free radicals with consequent oxidative stress and cell toxicity. Many aspects of CAA in early- and lateonset AD ‒the special preference of Aβ40 to deposit in the vessel walls, the favored vascular compromise associated with many Aβ genetic variants, the puzzling observation that some of these vasculotropic variants solely manifest with recurrent hemorrhagic episodes while others are mainly associated with dementia‒ await clarifi cation. Non-Aβ cerebral amyloidoses reinforce the viewpoint that plaque burden is not indicative of dementia while highlighting the relevance of non-fi brillar lesions and vascular involvement in the disease pathogenesis. The lessons learned from the comparative study of Aβ and non-Aβ cerebral amyloidosis provide new avenues and alternative models to study the role of amyloid in the molecular basis of neurodegeneration., 弘前医学. 61(Suppl.), 2010, p.S111-S124

Amyloid molecules harboring pyroglutamate （pGlu） residue at the N-termini are considered to be important for the development of cerebral amyloidosis such as Alzheimer’s disease and thought to be either spontaneously generated or being catalyzed by glutaminyl cyclase. Familial British dementia （FBD） is an autosomal dominant form of dementia neuropathologically characterized by parenchymal amyloid and preamyloid deposits, extensive cerebral amyloid angiopathy, and neurofi brillary tangles. FBD is caused by a stop to Arg mutation in the BRI2 gene, generating de novo created amyloid molecule ABri which accumulates in FBD brains but is not present in the normal population. Soluble ABri molecules present in the circulation of carriers of the BRI2 mutation are 34 amino acids long exclusively harboring Glu residue at the N-termini （ABri1-34E）, whereas water- and formic acidsoluble ABri molecules extracted from FBD brains have abundant ABri species bearing pGlu residue （ABri1-34pE）, suggesting that pyroglutamate formation occurs at the site of deposition. In order to further clarify the mechanism（s） of ABri deposition, we studied whether pyroglutamate formation indeed occurs outside the central nervous system taking advantage that FBD is also a systemic amyloidosis. Soluble and fibrillar ABri molecules extracted from systemic organs and analyzed biochemically using a combination of immunoprecipitation, mass spectrometry, and western blot analysis were oligomeric in size and contained a large proportion of ABri1-34pE. The data indicate that pyroglutamate formation at the N-termini of ABri molecules is an early step in the process of FBD amyloid deposition, and its formation is not restricted to the central nervous system., 弘前医学. 61(Suppl.), 2010, p.S262-S269

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