| 1. |
- Philipson, Ola, 1979-, et al.
(författare)
-
Biochemical and morphological analyses of Aβ deposits in postmortem brain of Arctic APP mutation carriers
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The clinical symptoms associated with the Arctic (E693G) mutation in the amyloid-β precursor protein (APP) are those of typical Alzheimer’s disease (AD), beginning with insidious loss of recent memories. However, an unusual neuropathology of ring-like amyloid-β (Aβ) plaques is identified in postmortem brain. Here, the neuropathology of subjects carrying the Arctic mutation was compared to that of sporadic AD. Different types of Aβ-deposits were examined with light, confocal and electron microscopy, and their composition was analyzed with biochemical techniques. Parenchymal deposits of the Arctic mutant brain were homogenous in structure, lacked an amyloid core and were immunostained differentially by antibodies recognizing C- or N-terminal epitopes of Aβ. Superficially, Arctic Aβ plaques bore considerable resemblance to cotton wool plaques (CWP), namely their large size, the presence of healthy neuronal nuclei and the absence of marked neuritic dystrophy within the plaques, and the sparsity of astro- or microgliosis in the surrounding tissue. Both parenchymal deposits and cerebral amyloid angiopathy of Arctic mutant brain contained a mixture of Arctic and wild-type Aβ. While Aβ peptides in parenchymal plaques were often N-terminally truncated, a substantial amount of full-length Aβ1-40 was deposited in the vessel walls as cerebral amyloid angiopathy (CAA). Thus, the absence of amyloid cores in parenchymal plaques of Arctic mutant brain was likely due to the scarcity of full-length Aβ species, although other mechanisms could also be involved. Our findings are discussed in relation to the clinical features of patients carrying the Arctic mutation and neuropathological observations made with other intra-Aβ mutations in human and transgenic mouse brain.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Lord, Anna, 1979-, et al.
(författare)
-
Arctic Aβ selectively increases diffuse deposition of wild type Aβ in APP transgenic mice with the Swedish mutation
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Studies of familial Alzheimer´s disease (AD) suggest that misfolding and aggregation of amyloid-β (Aβ) peptides initiate the pathogenesis, which causes dementia. The Arctic amyloid precursor protein (APP) mutation results in AD, and Arctic Aβ is more prone to form Aβ protofibrils. Here we show that the number of diffuse Aβ deposits, but not amyloid plaques, is increased if tg-ArcSwe mice synthesizing a low level of Arctic Aβ are crossed with plaque-depositing tg-Swe mice. The diffuse deposits in bitransgenic mice, which contain mainly wild type Aβ42, accumulate in regions both with and without transgene expression. The selective increase of a single type of parenchymal Aβ deposit suggest that different pathways of Aβ aggregation lead to the formation of diffuse and compact Aβ deposits in the brain. The raise in diffuse deposits is most likely due to direct physical interactions between Arctic and wild type Aβ42, and not to altered APP processing in young bitransgenic mice. A mixture of Arctic and wild type Aβ42 facilitates the formation of prefibrillar and fibrillar Aβ assemblies, but inhibits the further elongation of Aβ fibrils in vitro. Our findings might have implications to the pathogenesis of patients who are heterozygous for the Arctic mutation. It also further illustrates how Aβ neuropathology can be manipulated in vivo in a manner reminiscent to prion disorders.
|
|
| 6. |
|
|
| 7. |
- Degerman Gunnarsson, Malin, et al.
(författare)
-
Re-evaluation of clinical dementia diagnoses with PET-PIB
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: There is an overlap regarding Pittsburgh Compound-B (PIB) retention in patients clinically diagnosed as Alzheimer’s disease (AD) and non-AD dementia. The aim of the present study was to investigate whether there are any differences between PIB+ and PIB PIB- patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with 18 Fluoro-2-deoxy-d-glucose (FDG) PET.Methods: Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting.Results: The PIB+ patients (7/18) had slower psychomotor speed and more impaired visual episodic memory than the PIB- patients, otherwise performance did not differ between groups. The initial clinical diagnoses were changed in one third of the patients (6/18) during follow-up. Conclusions: The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need of amyloid biomarkers and readiness to re-evaluate the initial diagnosis.
|
|
| 8. |
- Emami Khoonsari, Payam, et al.
(författare)
-
Chitinase-3-like protein 1 (CH3L1) and Neurosecretory protein VGF (VGF) as two novel CSF biomarker candidates for improved diagnostics in Alzheimer’s disease
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition and accumulation of intracellular neurofibrillary tangles. This pathology is mirrored in the cerebrospinal fluid (CSF), where decreased Aβ42 together with increased total (t-tau) and phospho-tau (p-tau) today is used as a diagnostic marker. Although these biomarkers have a fairly good sensitivity and specificity, additional biomarkers are needed to further improve the accuracy for early disease detection and to monitor disease development. In this study, we used mass spectrometry-based shotgun proteomics to investigate the CSF proteome of patients with AD and mild cognitive impairment (MCI) as well as of non-demented controls. By combining the diagnostic markers (Aβ42, total t-tau, and p-tau) with a selection of proteomics biomarkers, the accuracy of predicting MCI to AD conversion increased from 83% to 92% with a specificity of 1.0 and sensitivity of 0.86. Among these markers, the levels of protein chitinase-3-like protein 1 (CH3L1) were significantly higher in AD and MCI converters compared to controls. In addition to Aβ42, t-tau, and p-tau the protein CH3L1 contributed mostly to the prediction accuracy. We also found statistically significant lower CSF levels of the neurosecretory protein VGF (VGF) in AD compared to controls. Taken together, our findings suggest that incorporating new CSF biomarkers can further enhance early diagnosis of AD.
|
|
| 9. |
|
|
| 10. |
- O'Callaghan, Paul, et al.
(författare)
-
Apolipoprotein-E increases cell-associated amyloid-β through a heparan sulfate-dependent pathway
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The increased risk of Alzheimer’s disease (AD) associated with specific apolipoprotein E (ApoE) isoforms appears to relate to altered amyloid-β (Aβ) homeostasis. The efficiency of Aβ clearance from the brain is reduced in the presence of the AD-associated ApoE4 isoform, which may explain the accumulation of Aβ deposits in the parenchyma and vasculature. The low density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs) are involved in Aβ uptake, with LRP1 further implicated in Aβ transcytosis across the blood brain barrier. However, both are also established ApoE receptors and function co-operatively to mediate cell interactions with lipoproteins and Aβ. Here we determined that HS, ApoE and LRP1 co-occur in Aβ40-positive microvessels of AD brain, establishing the relevance of studying interactions between these molecules. Using Chinese hamster ovary (CHO) cells deficient in HS or LRP1 we found that ApoE increases the levels of cell-associated Aβ in primarily a HSPG-dependent manner. Furthermore, in this model we found that ApoE is alternatively processed in the absence of cell surface HS, supporting a role for HSPGs in ApoE metabolism. The findings presented here raise the possibility that ApoE can increase Aβ associations with HSPGs and LRP1 in the vasculature. This may facilitate clearance, but if unbalanced could contribute to Aβ accumulation and the pathogenesis of AD.
|
|
