Bri1 gene-related dementias; A morphological and biochemical study.

Aspects of the neurodegenerative mechanism in AD remain unknown therefore studies on alternative models of cerebral amyloidosis, such as familial British dementia (FBD) and familial Danish dementia (FDD) may contribute to a better understanding of the neurodegenerative process. FBD and FDD are neurodegenerative disorders caused by mutations in the BRI2 gene. Both mutations cause elongation of the precursor proteins, the furin-like cleavage of which results in the formation of amyloidogenic peptides, ABri in FBD and ADan in FDD. Extensive morphological examinations of FBD and FDD were undertaken using antibodies recognising ABri and ADan, establishing a regional distribution of CNS peptide deposits in either amyloid or pre-amyloid configuration in both diseases, including cerebral amyloid angiopathy (CAA) formation. Amyloid associated proteins (AAP) are able to modify Afi aggregation and are implicated in AD pathogenesis. Establishing whether AAPs are implicated in the pathogenesis of other cerebral amyloidoses, AAP deposition was investigated and found associated with ABri and ADan amyloid and preamyloid parenchymal lesions. Inflammatory mechanisms, including activation of the complement pathways, initiated by AJ3 deposition strongly are implicated in AD pathogenesis. The presence of the complement pathways were shown in FBD and FDD, highlighting the importance of chronic inflammation in the neurodegenerative diseases. Biochemical analysis of extracted ABri and ADan species indicates that as solubility of the deposits decrease heterogeneity and complexity of extracted peptides increases, including post-translational modification of glutamate to pyroglutamate. The production and cellular origin of the precursor proteins and the localisation of fiirin expression were investigated. Evidence is presented that BRI2 mRNA and furin are found in neurons and glia, suggesting that cleavage of the wild type and mutated precursor proteins can take place in these cells. The absence of BRI2 mRNA in cerebrovascular cells indirectly supports the drainage hypothesis of CAA

Experimental electronic heat capacities of α−\alpha- and δ−\delta-Plutonium; heavy-fermion physics in an element

We have measured the heat capacities of $\delta-$Pu$_{0.95}$Al$_{0.05}$ and $\alpha-$Pu over the temperature range 2-303 K. The availability of data below 10 K plus an estimate of the phonon contribution to the heat capacity based on recent neutron-scattering experiments on the same sample enable us to make a reliable deduction of the electronic contribution to the heat capacity of $\delta-$Pu$_{0.95}$Al$_{0.05}$; we find $\gamma = 64 \pm 3$ mJK$^{-2}$mol$^{-1}$ as $T \to 0$. This is a factor $\sim 4$ larger than that of any element, and large enough for $\delta-$Pu$_{0.95}$Al$_{0.05}$ to be classed as a heavy-fermion system. By contrast, $\gamma = 17 \pm 1$ mJK$^{-2}$mol$^{-1}$ in $\alpha-$Pu. Two distinct anomalies are seen in the electronic contribution to the heat capacity of $\delta-$Pu$_{0.95}$Al$_{0.05}$, one or both of which may be associated with the formation of the $\alpha'-$ martensitic phase. We suggest that the large $\gamma$-value of $\delta-$Pu$_{0.95}$Al$_{0.05}$ may be caused by proximity to a quantum-critical point.Comment: 4 pages, 4 figure

Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer's Disease

Amyloid-related imaging abnormalities (ARIA), thought to reflect immune responses to vascular amyloid, have been detected in several amyloid-modifying therapy trials for Alzheimer's disease (AD). We report a case of ARIA developing spontaneously during the course of Presenilin 1 (PSEN1)-associated familial AD (FAD), in an APOE4 homozygous patient. Severe cerebral amyloid angiopathy with associated inflammation was subsequently found at autopsy. Recognition that ARIA may arise spontaneously during FAD and of the potential risk factors for its development are important observations given the recent launch of amyloid-modifying therapy trials for FAD

Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases

Heterogenous nuclear ribonucleoproteins (hnRNPs) are a complex and functionally diverse family of RNA binding proteins with multifarious roles. They are involved, directly or indirectly, in alternative splicing, transcriptional and translational regulation, stress granule formation, cell cycle regulation, and axonal transport. It is unsurprising, given their heavy involvement in maintaining functional integrity of the cell, that their dysfunction has neurological implications. However, compared to their more established roles in cancer, the evidence of hnRNP implication in neurological diseases is still in its infancy. This review aims to consolidate the evidences for hnRNP involvement in neurological diseases, with a focus on spinal muscular atrophy (SMA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), congenital myasthenic syndrome (CMS), and fragile X-associated tremor/ataxia syndrome (FXTAS). Understanding more about hnRNP involvement in neurological diseases can further elucidate the pathomechanisms involved in these diseases and perhaps guide future therapeutic advances

Temporal Variant Frontotemporal Dementia Is Associated with Globular Glial Tauopathy

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disorder associated with atrophy of the frontal and temporal lobes. Most patients with focal temporal lobe atrophy present with either the semantic dementia subtype of FTD or the behavioral variant subtype. For patients with temporal variant FTD, the most common cause found on post-mortem examination has been a TDP-43 (transactive response DNA-binding protein 43 kDa) proteinopathy, but tauopathies have also been described, including Pick’s disease and mutations in the microtubule-associated protein tau (MAPT) gene. We report the clinical and imaging features of 2 patients with temporal variant FTD associated with a rare frontotemporal lobar degeneration pathology known as globular glial tauopathy. The pathologic diagnosis of globular glial tauopathy should be considered in patients with temporal variant FTD, particularly those who have atypical semantic dementia or an atypical parkinsonian syndrome in association with the right temporal variant

Variability in the type and layer distribution of cortical A beta pathology in familial Alzheimer's disease

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre-codon 200 (n = 10), PSEN1 post-codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid-beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub-group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post-codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post-codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

Dysregulated RNA metabolism is emerging as a crucially important mechanism underpinning the pathogenesis of frontotemporal dementia (FTD) and the clinically, genetically and pathologically overlapping disorder of amyotrophic lateral sclerosis (ALS). Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins with diverse, multi-functional roles across all aspects of mRNA processing. The role of these proteins in neurodegeneration is far from understood. Here, we review some of the unifying mechanisms by which hnRNPs have been directly or indirectly linked with FTD/ALS pathogenesis, including their incorporation into pathological inclusions and their best-known roles in pre-mRNA splicing regulation. We also discuss the broader functionalities of hnRNPs including their roles in cryptic exon repression, stress granule assembly and in co-ordinating the DNA damage response, which are all emerging pathogenic themes in both diseases. We then present an integrated model that depicts how a broad-ranging network of pathogenic events can arise from declining levels of functional hnRNPs that are inadequately compensated for by autoregulatory means. Finally, we provide a comprehensive overview of the most functionally relevant cellular roles, in the context of FTD/ALS pathogenesis, for hnRNPs A1-U

Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan

Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and Aβ in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Clusterin is known to bind soluble Aβ in biological fluids, facilitate its brain clearance, and prevent its aggregation. The current work identifies clusterin as the major ABri- and ADan-binding protein and provides insight into the biochemical mechanisms leading to the association of clusterin with ABri and ADan deposits. Mirroring findings in AD, the studies corroborate clusterin co-localization with cerebral parenchymal and vascular amyloid deposits in both disorders. Ligand affinity chromatography with downstream Western blot and amino acid sequence analyses unequivocally identified clusterin as the major ABri- and ADan-binding plasma protein. ELISA highlighted a specific saturable binding of clusterin to ABri and ADan with low nanomolar Kd values within the same range as those previously demonstrated for the clusterin-Aβ interaction. Consistent with its chaperone activity, thioflavin T binding assays clearly showed a modulatory effect of clusterin on ABri and ADan aggregation/fibrillization properties. Our findings, together with the known multifunctional activity of clusterin and its modulatory activity on the complex cellular pathways leading to oxidative stress, mitochondrial dysfunction, and the induction of cell death mechanisms – all known pathogenic features of these protein folding disorders – suggests the likelihood of a more complex role and a translational potential for the apolipoprotein in the amelioration/prevention of these pathogenic mechanisms