| 1. |
- Antonios, Gregory, et al.
(author)
-
N-truncated Abeta starting with position four : early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody
- 2013
-
In: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 1:1, s. 56-
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1-42 and Aβ1-40, N-truncated AβpE3-42 and Aβ4-42 are major variants in AD brain. Although Aβ4-42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4-42 may precede the other in Alzheimer's disease pathology.RESULTS: Using different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4-42 toxicity in vitro no beneficial effect was observed against Aβ1-42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD.CONCLUSIONS: Aβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research.
|
|
| 2. |
|
|
| 3. |
- Edvinsson, Benjamin, et al.
(author)
-
Toxoplasmosis in immunocompromized patients
- 2009
-
In: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 41:5, s. 368-371
-
Journal article (peer-reviewed)abstract
- Infection with the cosmopolitan parasite Toxoplasma gondii is often associated with severe consequences and a high mortality rate in immunocompromized patients. Non-specific symptoms make diagnosis challenging. Monitoring of patients at risk is of value. We here present 8 cases of toxoplasmosis in immunocompromized patients with suggestions for preventive monitoring.
|
|
| 4. |
- Guzman, Erika Avendano, et al.
(author)
-
Abundance of A beta(5-x) x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease
- 2014
-
In: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9, s. 13-
-
Journal article (peer-reviewed)abstract
- Background: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptide (A beta) within neurons. Additionally to full-length peptides, a great diversity of N-truncated A beta variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that A beta(x-42) isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and A beta(x-42) species have been pointed as crucial players in AD etiology, the A beta(5-x) isoforms have not received much attention. Results: The present study is the first to show immunohistochemical evidence of A beta(5-x) in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe A beta(5-x) peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of A beta(5-x) distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular A beta deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal A beta(5-x). Conclusions: Different degrees of A beta(5-x) accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular A beta(5-x), these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher A beta(5-x)-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving A beta(5-x) peptides and operating in a divergent way in the late and early onset forms of the disease.
|
|
| 5. |
- Götz, Alexandra, et al.
(author)
-
Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy
- 2011
-
In: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 88:5, s. 635-642
-
Journal article (peer-reviewed)abstract
- Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.
|
|
| 6. |
- Hooshmand, Babak, et al.
(author)
-
Plasma homocysteine, Alzheimer and cerebrovascular pathology : a population-based autopsy study
- 2013
-
In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 136, s. 2707-2716
-
Journal article (peer-reviewed)abstract
- Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer's disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged epsilon 85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-beta and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, cerebral amyoloid angiopathy, and alpha-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28-5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-beta accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88-7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12-12.79) for more severe medial temporal atrophy and 4.69 (1.14-19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or alpha-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged epsilon 85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed to determine the impact of homocysteine-lowering treatments on dementia-related pathology.
|
|
| 7. |
- Peuralinna, Terhi, et al.
(author)
-
Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein
- 2008
-
In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 64:3, s. 348-352
-
Journal article (peer-reviewed)abstract
- We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical beta-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration.
|
|
| 8. |
- Rauramaa, Tuomas, et al.
(author)
-
Cardiovascular diseases and hippocampal infarcts
- 2011
-
In: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 21:3, s. 281-287
-
Journal article (peer-reviewed)abstract
- The prevalence of hippocampal lesions such as hippocampal infarcts have not been studied in detail even though hippocampal alterations are known to be associated with various clinical conditions such as age-related degenerative disorders and epilepsy. Methods: Here we defined the hippocampal infarcts and assessed the prevalence of this lesion in large unselected population of 1,245 subjects age ranging from 1 to 99 years (mean age 79 +/- 1 S.E.M). Furthermore, we assessed the association of these lesions with various cardio- and cerebro-vascular disorders and other neurodegenerative lesions. The prevalence of hippocampal infarct in the study population of 1,245 subjects was 12%, increasing to 13% when only those with a clinically diagnosed cognitive impairment (n = 311) were analyzed. Large hemispheric brain infarcts were seen in 31% of the study subjects and these lesions were strongly associated with cardiovascular risk factors such as hypertension (43%), coronary disease (32%), myocardial infarct (22%), atrial fibrillation (20%), and heart failure (20%). In contrast, hippocampal infarcts displayed a significant association only with large hemispheric brain infarct, heart failure, and cardiovascular index as assessed postmortem. It is noteworthy that only widespread hippocampal infarcts were associated with clinical symptoms of cognitive impairment or epilepsy. The surprisingly low prevalence of 12% of hippocampal infarcts in aged population found here and the failure to detect an association between this lesion and various cerebro- cardio-vascular lesions is intriguing. Whether susceptibility to ischemia in line with susceptibility to neuronal degeneration in this region is influenced by still undetermined risk- factors need further investigation. Furthermore it should be noted that the size of the hippocampal tissue damage, i.e., small vs. large cystic infarcts is of significance regarding clinical alterations.
|
|
| 9. |
- Rauramaa, Tuomas, et al.
(author)
-
Consensus Recommendations on Pathologic Changes in the Hippocampus : A Postmortem Multicenter Inter-Rater Study
- 2013
-
In: Journal of Neuropathology and Experimental Neurology. - 0022-3069 .- 1554-6578. ; 72:6, s. 452-461
-
Journal article (peer-reviewed)abstract
- There is no consensus on the pathologic conditions or severity implied by the term "hippocampal sclerosis" (HS). In this study, a panel of experienced neuropathologists evaluated inter-rater agreement for pathologic diagnoses in the hippocampus and proposes consensus recommendations on the use of the term "HS." In a group of 251 cases of HS selected from a large autopsy cohort (1,388; 18%), a coordinating group identified 5 patterns of degenerative or vascular pathology. Four independent neuropathologists assessed a single set of hematoxylin and eosin-stained sections following descriptive definitions to classify the appearances and assign the diagnosis of HS, if appropriate. Diagnostic agreement (range, 36%-70%) was highest for vascular lesions. Subsequent joint review of all cases highlighted the need to identify neurodegenerative lesions using immunohistochemistry. Initial agreement in assigning the diagnosis of HS varied from 0% to 86%. After a joint review, the group recommended that the term "HS" should be applied to all cases with complete/near-complete neuronal loss and gliosis in the subfields of the cornu Ammonis but not to hippocampal microinfarction. Therefore, the etiology of HS must be defined in association with a neurodegenerative process or as "lacking neurodegenerative markers," a pathologic condition presumed to arise from hypoxic/ischemic mechanisms.
|
|
| 10. |
- Rauramaa, Tuomas, et al.
(author)
-
TAR-DNA binding protein-43 and alterations in the hippocampus
- 2011
-
In: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 118:5, s. 683-689
-
Journal article (peer-reviewed)abstract
- Immunocytochemistry for transactive response binding protein-43 (TDP43) was assessed in the granular cell layer of the dentate gyrus in 250 cases displaying hippocampal pathology identified by haematoxylin-eosin staining. 18%, nearly one in five displayed TDP43 immunoreactive pathology in the granular cell layer of hippocampus. This percentage increased to 43% when only subjects with hippocampal pathology other than vascular in origin were included. When only subjects with severe Alzheimer's disease-related pathology were included, 42% displayed TDP43-immunoreactive pathology, increasing to 60% when concomitant Alzheimer's disease and alpha-synuclein pathology were present. Within this setting, TDP43-immunoreactive pathology was observed to be present in 6% of subjects with hippocampal pathology but without any cognitive impairment. Our findings justify assessment of TDP43 pathology in every case where a pathological alteration is observed in the hippocampus using a routine stain.
|
|
