Marie Bojsen-Møller

Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques.

Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and β-amyloid (Aβ)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with Aβ-(1-42) and Aβ-(4-42) in ∼1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas Aβ was mainly Aβ-(4-42). In all cases, the presence of Aβ-(X-40) was negligible, a surprising finding in view of the prevalence of Aβ40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and Aβ molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neuro fibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.

Complement Activation in Chromosome 13 Dementias SIMILARITIES WITH ALZHEIMER'S DISEASE

Chromosome 13 dementias, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with neurodegeneration and cerebrovascular amyloidosis, with striking neuropathological similarities to Alzheimers disease (AD). Despite the structural differences among the amyloid subunits (ABri in FBD, ADan in FDD, and Aβ in AD), these disorders are all characterized by the presence of neurofibrillary tangles and parenchymal and vascular amyloid deposits co-localizing with markers of glial activation, suggestive of local inflammation. Proteins of the complement system and their pro-inflammatory activation products are among the inflammation markers associated with AD lesions. Immunohistochemistry of FBD and FDD brain sections demonstrated the presence of complement activation components of the classical and alternative pathways as well as the neo-epitope of the membrane attack complex. Hemolytic experiments and enzyme-linked immunosorbent assays specific for the activation products iC3b, C4d, Bb, and C5b-9 indicated that ABri and ADan are able to fully activate the complement cascade at levels comparable to those generated by Aβ1–42. ABri and ADan specifically bound C1q with high affinity and formed stable complexes in physiological conditions. Activation proceeds ∼70–75% through the classical pathway while only ∼25–30% seems to occur through the alternative pathway. The data suggest that the chronic inflammatory response generated by the amyloid peptides in vivo might be a contributing factor for the pathogenesis of FBD and FDD and, in more general terms, to other neurodegenerative conditions.

Genetic Alterations of the BRI2 gene: Familial British and Danish Dementias

Classic arguments sustaining the importance of amyloid in the pathogenesis of dementia are usually centered on amyloid β (Aβ) and its role in neuronal loss characteristic of Alzheimer disease, the most common form of human cerebral amyloidosis. Two non‐Aβ cerebral amyloidoses, familial British and Danish dementias, share many aspects of Alzheimer disease, including the presence of neurofibrillary tangles, parenchymal pre‐amyloid and amyloid deposits, cerebral amyloid angiopathy, and a widespread inflammatory response. Both early‐onset conditions are linked to specific mutations in the BRI2 gene, causing the generation of longer‐than‐normal protein products and the release of 2 de novo created peptides ABri and ADan, the main components of amyloid fibrils in these inherited dementias. Although the molecular mechanisms and signal transduction pathways elicited by the amyloid deposits and their relation to cognitive impairment remain to be clarified, new evidence indicates that, independent of the differences in their primary structures, Aβ, ABri, and ADan subunits are able to form morphologically compatible ion‐channel‐like structures and elicit single ion‐channel currents in reconstituted lipid membranes. These findings reaffirm the notion that non‐ Aβ amyloidosis constitute suitable alternative models to study the role of amyloid deposition in the mechanism of neuronal cell death.

Chromosome 13 dementia syndromes as models of neurodegeneration

Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylatedtau immunoreactivity is almost indistinguishable from that seen in Alzheimers disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.

Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene-related dementias: a morphological study.

Molecular chaperons or amyloid‐associated proteins (AAPs) are deposited in vascular and parenchymal amyloid lesions in Alzheimer’s disease (AD) and other amyloidoses. AAPs, such as apolipoprotein E (ApoE) or apolipoprotein J (ApoJ) have been strongly implicated in the pathogenesis of AD in vitro and in vivo. Furthermore the possession of the ApoE ∈4 allele is a well‐studied risk factor for AD. In view of the similarities between AD and both familial British dementia (FBD) and familial Danish dementia (FDD), we investigated the presence of AAPs in these two diseases to understand better their role in the general process of amyloidogenesis. Immunohistochemistry for ApoE, ApoJ, serum amyloid P (SAP), alpha‐1‐antichymotrypsin, cystatin C, heparan sulphate proteoglycans, such as agrin, perlecan, syndecans, glypican‐1 and for heparan sulphate glycosaminoglycan (HS GAG) side chains was carried out together with immunohistochemical preparations specific to the amyloid subunits. Significant or extensive staining for ApoE, ApoJ, agrin, glypican‐1 and HS GAG side chains was found in both amyloid (fibrillar) and preamyloid (nonfibrillar) deposits in FBD and FDD. The remaining AAPs, including SAP, were predominantly found in amyloid lesions. Only very weak staining was present in a small proportion of the amyloid lesions using perlecan immunohistochemistry. These findings suggest that the deposition patterns of AAPs in FBD and FDD are mostly similar to those in AD. The presence of AAPs in the preamyloid lesions supports the notion that chaperon molecules may play a role in the early steps of fibrillogenesis.

Preferential association of serum amyloid P component with fibrillar deposits in familial British and Danish dementias: Similarities with Alzheimer's disease

Two hereditary forms of cerebrovascular amyloidosis, familial British and Danish dementias (FBD and FDD), share striking similarities with Alzheimers disease (AD) despite structural differences among their amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD). Neuropathological lesions in these disorders include neurofibrillary tangles, parenchymal amyloid and pre-amyloid deposits and overwhelming cerebral amyloid angiopathy co-localizing with reactive microglia and multiple amyloid associated proteins including activation products of the complement cascade. Immunohistochemical analysis of FBD and FDD brain lesions unveiled the presence of serum amyloid P-component (SAP) primarily associated with thioflavin positive amyloid deposits in spite of the significant pre-amyloid burden existing in both disorders. Using affinity chromatography and ELISA binding assays we demonstrated specific, calcium-dependent, saturable, high affinity binding interactions between SAP and ABri/ADan peptides, with dissociation constant values in the sub-nanomolar range and within the same order of magnitude as those resulting from the interaction of SAP with Alzheimers Abeta1-40 and Abeta1-42. The preferential association of SAP with fibrillar amyloid lesions and not with non-fibrillar pre-amyloid deposits is puzzling, suggesting that SAP modulates the assembly and stability of the final fibril rather than participating in the early steps of protein misfolding and oligomerization.

‘Melanosis of the dentate nucleus’: A widespread disorder of protoplasmic astrocytes

SummarySeven cases of so-called melanosis of the dentate nucleus are reported, 6 of them females and all but one over 49 years of age. The neuromelanin-like pigment seemed to be derived from lipofuscin in protoplasmic astrocytes and in 4 of the cases it was present in cerebral grey matter, mainly cortical, in addition to the cerebellum. The intensity of pigmentation and granule size in the different sites suggested that it could have developed sequentially, first in the dentate nucleus, then in the cerebellar granular layer and ultimately in the cerebral grey matter from occipital cortex forward. the melanosis appeared not to give rise to clinically recognisable functional effects and there was no other consistently associated disease process.

Clinical and pathological features of frontotemporal lobar degeneration with FUS-positive inclusions

to conventional pharmacotherapy. We studied a specific omega-3 fatty acid, the ethyl ester of eicosapentaenoic acid (E-EPA), as an adjunct to antidepressant treatment for episodes of depressive disorder occurring in older depressed patients(over 60 years old) with or without executive dysfunction. Methods: The design was a 12-week, parallel-group, double-blind addition of E-EPA or placebo to ongoing antidepressant therapy. Patients continued their current antidepressant treatment at the same dose they were receiving when they entered the study. The E-EPA or matching placebo was given in 1-g doses twice a day for a total of 2 g/day. Executive functions were assessed with Controlled Oral Word Association Test and the Korean Stroop Color-Word Test and Trail Making Test part B. Depressive symptoms were measured by Korean Geriatric depression Scale(K-GDS), Quick Inventory of Depressive Symptomtology-Self Report(QIDS-SR). Results: Eighty six patients participated. A total of 52 patients completed the study. At endpoint (12 weeks), the mean change from baseline in QIDS-SR total score was -20.2 for patients treated with placebo (n1⁄4 23) and -23.5 for patients with EEPA (n1⁄4 29), resulting in no difference. But, both abnormal Controlled oral word association test and abnormal Stroop Color-Word scores were associated with an favorable response of geriatric depression to E-EPA addition treatment. Conclusions: Improvement of frontal lobe dysfunction were found after supplementation of omega-3 fatty acid in geriatric depressive patients with executive dysfunction.