β-catenin mutations in craniopharyngiomas and pituitary adenomas

Craniopharyngiomas and pituitary adenomas are both tumors of the hypothalamic and pituitary region, respectively that are frequently associated with endocrine defects either because of direct involvement of hormone producing cells (most pituitary tumors) or because of secondary defects due to disturbance of hypothalamic function (some pituitary tumors and craniopharyngiomas). Some studies suggest that mutant β-catenin gene cells in craniopharyngiomas and pituitary adenomas contribute to their tumorigenesis. DNA was extracted from 73 cranial tumors and subjected to polymerase chain reaction (PCR) with previously described primers encompassing glycogen synthase kinase-3β phosphorylation sites of the β-catenin gene. Sequenced PCR products for possible β-catenin gene mutations showed a total of 7/43 alterations in adamantinomatous craniopharyngioma-derived DNA samples. Two previously described β-catenin mutations in codon 33 TCT(Ser) > TGT(Cys) and codon 37 TCT(Ser) > TTT(Phe), whereas three novel mutations in codon 41 ACC(Thr) > ATC(Ile), codon 33 TCT(Ser) > TAT(Tyr) and codon 32 GAC(Asp) > AAC(Asn) were observed. None of the 22 pituitary adenomas and the eight papillary craniopharyngiomas analyzed presented any sequence alterations. These findings demonstrate an association between β-catenin gene alterations and craniopharyngiomas of the adamantinomatous type. Since this gene product is involved with development, these results suggest that β-catenin mutations may contribute to the initiation and subsequent growth of congenital craniopharyngiomas. © Springer 2005.

Plaques and tangles and the pathogenesis of Alzheimer's disease

Since the earliest descriptions, senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the pathological hallmarks of Alzheimer's disease (AD). Consequently, studies of the morphology, distribution, and molecular composition of SP and NFT have played an important role in developing theories as to the pathogenesis of AD; the most important being the 'Amyloid Cascade Hypothesis (ACH)'. Nevertheless, the significance of SP and NFT to the pathogenesis of AD remains controversial. This review examines three questions: 1) is there a relationship between the lesions and the degree of clinical dementia, 2) is the pathogenesis of the NFT linked to that of the SP, and 3) what is the relationship of SP and NFT to the pathogenesis of AD? These questions are discussed with reference to the morphology and molecular composition of SP and NFT, the effects of gene mutations, studies of head injury patients, experimental studies involving brain lesions and transgenes, and the degeneration of specific anatomical pathways. It was concluded that SP and NFT are not closely related to the developing dementia in AD, arise as relatively independent lesions, and may be the products of a degenerative process rather than being their cause.

Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration?

Pathological lesions in the form of extracellular protein deposits, intracellular inclusions and changes in cell morphology occur in the brain in the majority of neurodegenerative disorders. Studies of the presence, distribution, and molecular determinants of these lesions are often used to define individual disorders and to establish the mechanisms of lesion pathogenesis. In most disorders, however, the relationship between the appearance of a lesion and the underlying disease process is unclear. Two hypotheses are proposed which could explain this relationship: (i) lesions are the direct cause of the observed neurodegeneration ('causal' hypothesis); and (ii) lesions are a reaction to neurodegeneration ('reaction' hypothesis). These hypotheses are considered in relation to studies of the morphology and molecular determinants of lesions, the effects of gene mutations, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies and the degeneration of anatomical pathways. The balance of evidence suggests that in many disorders, the appearance of the pathological lesions is a reaction to degenerative processes rather than being their cause. Such a conclusion has implications both for the classification of neurodegenerative disorders and for studies of disease pathogenesis.

Spatial correlations between beta-amyloid (A beta) deposits and blood vessels in familial Alzheimer's disease

In sporadic Alzheimer’s disease (SAD), the classic (‘dense-cored’) ß-amyloid (Aß) deposits are aggregated around the larger blood vessels in the upper laminae of the cerebral cortex. To determine whether a similar relationship exists in familial AD (FAD), the spatial correlations between the diffuse, primitive, and classic ß-amyloid (Aß deposits and blood vessels were studied in ten FAD cases including cases linked to amyloid precursor protein (APP) and presenilin (PSEN) gene mutations and expressing apolipoprotein E (apo E) allele E4. Sections of frontal cortex were immunolabelled with antibodies against Aß and with collagen IV to reveal the Aß deposits and blood vessel profiles. In the FAD cases as a whole, Aßdeposits were distributed in clusters. There was a positive spatial correlation between the clusters of the diffuse Aßdeposits and the larger (>10 µm) and smaller diameter (<10 µm) blood vessels in one and three cases respectively. The primitive Aß deposits were spatially correlated with larger and smaller blood vessels each in four cases and the classic deposits in three and four cases respectively. Apo E genotype of the patient did not influence spatial correlation with blood vessels. Hence, spatial correlations between the classic deposits and larger diameter blood vessels were significantly less frequent in FAD compared with SAD. It was concluded that both Aß deposit morphology and AD subtype determine spatial correlations with blood vessels in AD.

What causes alzheimer's disease?

Since the earliest descriptions of Alzheimer's disease (AD), many theories have been advanced as to its cause. These include: (1) exacerbation of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3) an environmental factor such as exposure to aluminium, head injury, or malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes and allelic variation in apolipoprotein E (Apo E), (5) mitochondrial dysfunction, (6) a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these theories and concludes that AD is a multifactorial disorder in which genetic and environmental risk factors interact to increase the rate of normal aging ('allostatic load'). The consequent degeneration of neurons and blood vessels results in the formation of abnormally aggregated 'reactive' proteins such as ß-amyloid (Aß) and tau. Gene mutations influence the outcome of age-related neuronal degeneration to cause early onset familial AD (EO-FAD). Where gene mutations are absent and a combination of risk factors present, Aß and tau only slowly accumulate not overwhelming cellular protection systems until later in life causing late-onset sporadic AD (LO-SAD). Aß and tau spread through the brain via cell to cell transfer along anatomical pathways, variation in the pathways of spread leading to the disease heterogeneity characteristic of AD.

What risk factors are associated with Alzheimer's disease?

A large number of risk factors have been associated with Alzheimer’s disease (AD). This article discusses the validity of the major risk factors that have been identified including age, genetics, exposure to aluminium, head injury, malnutrition and diet, mitochondrial dysfunction, vascular disease, immune system dysfunction, and infection. Rare forms of early-onset familial AD (FAD) are strongly linked to the presence of specific gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factors associated with diet, the immune system, mitochondrial function, and infection may all be involved. Life-style changes that may reduce the effect of these risk factors and therefore, the risk of AD are discussed.

Risk factors for Alzheimer's disease

A large number of possible risk factors have been associated with Alzheimer'sdisease (AD).This chapter discusses the validity of the major risk factors that have been identifiedincluding age, genetics, exposure to aluminum, head injury, malnutrition and diet,mitochondrial dysfunction, vascular disease, immune system dysfunction, and infectionand proposes a hypothesis to explain how these various risk factors may cause ADpathology.Rare forms of early-onset familial AD (FAD) are strongly linked to the presence ofspecific gene mutations, viz. mutations in amyloid precursor protein (APP) andpresenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is amultifactorial disorder in which age-related changes, genetic risk factors, such as allelicvariation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factorsassociated with diet, immune system, mitochondrial function, and infection may all beinvolved.These risk factors interact to increase the rate of normal aging (=allostatic load')which over a lifetime results in degeneration of neurons and blood vessels and as aconsequence, the formation of abnormally aggregated =reactive' proteins such as ß-amyloid (Aß) and tau leading to the development of senile plaques (SP) andneurofibrillary tangles (NFT) respectively. Life-style changes that may reduce theallostatic load and therefore, the risk of dementia are discussed.

Receptor activity-modifying protein-dependent effects of mutations in the calcitonin receptor-like receptor:implications for adrenomedullin and calcitonin gene-related peptide pharmacology

Background and Purpose Receptor activity-modifying proteins (RAMPs) define the pharmacology of the calcitonin receptor-like receptor (CLR). The interactions of the different RAMPs with this class B GPCR yield high-affinity calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors. However, the mechanism for this is unclear. Experimental Approach Guided by receptor models, we mutated residues in the N-terminal helix of CLR, RAMP2 and RAMP3 hypothesized to be involved in peptide interactions. These were assayed for cAMP production with AM, AM2 and CGRP together with their cell surface expression. Binding studies were also conducted for selected mutants. Key Results An important domain for peptide interactions on CLR from I32 to I52 was defined. Although I41 was universally important for binding and receptor function, the role of other residues depended on both ligand and RAMP. Peptide binding to CLR/RAMP3 involved a more restricted range of residues than that to CLR/RAMP1 or CLR/RAMP2. E101 of RAMP2 had a major role in AM interactions, and F111/W84 of RAMP2/3 was important with each peptide. Conclusions and Implications RAMP-dependent effects of CLR mutations suggest that the different RAMPs control accessibility of peptides to binding residues situated on the CLR N-terminus. RAMP3 appears to alter the role of specific residues at the CLR-RAMP interface compared with RAMP1 and RAMP2. © 2013 The Authors. British Journal of Pharmacology published by John Wiley &. Sons Ltd on behalf of The British Pharmacological Society.

DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD):a study of the pathology of nine cases

Frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) is a neurodegenerative disease characterized by variable neocortical and allocortical atrophy principally affecting the frontal and temporal lobes. Histologically, there is neuronal loss, microvacuolation in the superficial cortical laminae, and a reactive astrocytosis. A variety of TDP-43 immunoreactive changes are present in FTLD-TDP including neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN) and, oligodendroglial inclusions (GI). Many cases of familial FTLD-TDP are caused by DNA mutations of the progranulin (GRN) gene. Hence, the density, spatial patterns, and laminar distribution of the pathological changes were studied in nine cases of FLTD-TDP with GRN mutation. The densities of NCI and DN were greater in cases caused by GRN mutation compared with sporadic cases. In cortical regions, the commonest spatial pattern exhibited by the TDP-43 immunoreactive lesions was the presence of clusters of inclusions regularly distributed parallel to the pia mater. In approximately 50% of cortical gyri, the NCI exhibited a peak of density in the upper cortical laminae while the GI were commonly distributed across all laminae. The distribution of the NII and DN was variable, the most common pattern being a peak of NII density in the lower cortical laminae and DN in the upper cortical laminae. These results suggest in FTLD-TDP caused by GRN mutation: 1) there are greater densities of NCI and DN than in sporadic cases of the disease, 2) there is degeneration of the cortico-cortical and cortico-hippocampal pathways, and 3) cortical degeneration occurs across the cortical laminae, the various TDP-43 immunoreactive inclusions often being distributed in different cortical laminae.