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1.  VEGF significantly restores impaired memory behavior in Alzheimer's mice by improvement of vascular survival 
Scientific Reports  2013;3:2053.
The functional impact of amyloid peptides (Aβs) on the vascular system is less understood despite these pathologic peptides are substantially deposited in the brain vasculature of Alzheimer's patients. Here we show substantial accumulation of Aβs 40 and 42 in the brain arterioles of Alzheimer's patients and of transgenic Alzheimer's mice. Purified Aβs 1–40 and 1–42 exhibited vascular regression activity in the in vivo animal models and vessel density was reversely correlated with numbers and sizes of amyloid plaques in human patients. A significant high number of vascular cells underwent cellular apoptosis in the brain vasculature of Alzheimer's patients. VEGF significantly prevented Aβ-induced endothelial apoptosis in vitro. Neuronal expression of VEGF in transgenic mice restored memory behavior of Alzheimer's. These findings provide conceptual implication of improvement of vascular functions as a novel therapeutic approach for the treatment of Alzheimer's disease.
PMCID: PMC3690383  PMID: 23792494
2.  Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer’s disease 
Acta neuropathologica  2010;120(2):185-193.
A proposed key event in the pathogenesis of Alzheimer’s disease (AD) is the formation of neurotoxic amyloid β (Aβ) oligomers and amyloid plaques in specific brain regions that are affected by the disease. The main plaque component is the 42 amino acid isoform of Aβ (Aβ1-42), which is thought to initiate plaque formation and AD pathogenesis. Numerous isoforms of Aβ, e.g., Aβ1-42, Aβ1-40 and the 3-pyroglutamate derivate of Aβ3-42 (pGluAβ3-42), have been detected in the brains of sporadic AD (SAD) and familial AD (FAD) subjects. However, the relative importance of these isoforms in the pathogenesis of AD is not fully understood. Here, we report a detailed study using immunoprecipitation in combination with mass spectrometric analysis to determine the Aβ isoform pattern in the cerebellum, cortex and hippocampus in AD, including subjects with a mutation in the presenilin (M146V) or amyloid precursor protein (KM670/671NL) genes, SAD subjects and non-demented controls. We show that the dominating Aβ isoforms in the three different brain regions analyzed from control, SAD, and FAD are Aβ1-42, pGluAβ3-42, Aβ4-42 and Aβ1-40 of which Aβ1-42 and Aβ4-42 are the dominant isoforms in the hippocampus and the cortex in all groups analyzed, controls included. No prominent differences in Aβ isoform patterns between FAD and SAD patients were seen, underscoring the similarity in the amyloid pathology of these two disease entities.
PMCID: PMC3568930  PMID: 20419305
Alzheimer’s disease; Amyloid precursor protein; Brain; Immunoprecipitation; Mass spectrometry
3.  Caspase-6 Activation in Familial Alzheimer Disease Brains Carrying Amyloid Precursor Protein, Presenilin I or Presenilin II Mutations 
We previously demonstrated the activation of Caspase-6 in the hippocampus and cortex in cases of mild, moderate, severe and very severe Alzheimer disease (AD). To determine whether Caspase-6 is also activated in familial AD, we performed an immunohistochemical analysis of active Caspase-6 and Tau cleaved by Caspase-6 in temporal cortex and hippocampal tissue sections from cases of familial AD. The cases included 5 carrying the amyloid precursor protein K670N, M671L Swedish mutation, 1 carrying the amyloid precursor protein E693G Arctic mutation, 2 each carrying the Presenilin I M146V, F105L, A431E, V261F, Y115C mutations, and 1 with the Presenilin II N141I mutation. Active Caspase-6 immunoreactivity was found in all cases. Caspase-6 immunoreactivity was observed in neuritic plaques or cotton wool plaques in some cases, neuropil threads and neurofibrillary tangles. These results indicate that Caspase-6 is activated in familial forms of AD, as previously observed in sporadic forms. Since sporadic and familial AD cases have similar pathological features, these results support a fundamental role of Caspase-6 in the pathophysiology of both familial and sporadic AD.
PMCID: PMC3079356  PMID: 19915487
Alzheimer disease; Arctic mutation; Casp6; Familial Alzheimer disease; Presenilin I mutation; Sporadic Alzheimer disease; Swedish mutation; Tau cleaved by Casp6
4.  Clinical and neuropathological features of the Arctic APP mutation causing early onset Alzheimer's disease 
Archives of neurology  2008;65(4):499-505.
A majority of mutations within the amyloid β (Aβ) region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral haemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-Aβ mutation to date causing the more typical clinical picture of Alzheimer's disease (AD).
To describe features of one Swedish and one American family with the previously reported Arctic APP mutation.
Affected and non-affected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, one brain from each family was investigated neuropathologically.
The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of AD and similar to the phenotype for other AD APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe, as demonstrated by magnetic resonance imaging and single photon emission computed tomography. One Swedish and one American case with the Arctic APP mutation have come to autopsy, neither of which showed any signs of haemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathology as well as abundant amyloid plaques. Intriguingly, a majority of plaques from both of these cases had a characteristic ring-like character.
Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with AD.
PMCID: PMC2723757  PMID: 18413473
Familial Alzheimer's disease; APP gene mutations; Arctic mutation; cerebral amyloid angiopathy; dementia; genealogy
5.  Staging of Neurofibrillary Pathology in Alzheimer's Disease: A Study of the BrainNet Europe Consortium 
It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and β-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-µm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V–VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I–II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers.
PMCID: PMC2659377  PMID: 18371174
Alzheimer's disease; immunohistochemistry; neurofibrillary pathology; neuropathological diagnosis; BrainNet Europe consortium
6.  Assessment of β-amyloid deposits in human brain: a study of the BrainNet Europe Consortium 
Acta Neuropathologica  2009;117(3):309-320.
β-Amyloid (Aβ) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as ι and α synuclein related lesions, also Aβ related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of Aβ, i.e. phase 1 = deposition of Aβ exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of Aβ phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of Aβ-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer’s disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the Aβ phase in AD is feasible even in large scale retrospective studies.
PMCID: PMC2910889  PMID: 19184666

Results 1-6 (6)