👤 Alisdair R Philp

Age-related macular degeneration (AMD) and Alzheimer's disease (AD) are neurodegenerative conditions that afflict millions of elderly people around the world. AMD is a progressive retinal disorder that leads to central vision loss whereas AD primarily causes cognitive decline and behavioral changes. While each disease has distinct clinical manifestations, the accumulation of extracellular amyloid-β is a common histopathologic finding. Similarly, cerebral amyloid angiopathy (CAA), a vascular condition that can exist independent or with AD, is characterized by the accumulation of amyloid-β in cerebral blood vessels. While significant investigation of the pathophysiologic links between AMD and AD has been conducted, the underlying similarities and differences in the pathobiology of AMD and CAA has not been considered. In this review, we discuss the common pathological features of these two conditions. We then discuss the similar pathobiology that involves cholesterol metabolism, apolipoprotein E, amyloid-β, and complement mediated inflammation. At the same time, we discuss key differences in their pathobiology. This discussion sheds new perspective and insights of their pathobiology. Show less

Bardet-Biedl syndrome (BBS) is an autosomal recessive disease characterized by retinal dystrophy, polydactyly, obesity, learning disabilities, renal involvement, and male hypogenitalism. BBS is genetically heterogeneous with mutations of 14 genes, accounting for approximately 70% of cases. Triallelic inheritance has been suggested in about 5% of cases. Forty-nine unrelated BBS patients were screened for mutations by DHPLC analysis in BBS1, BBS2, BBS4, BBS6/MKKS, BBS10, and BBS12. The selected genes either account for more than 5% of the mutational load or are commonly reported in triallelic inheritance. Eight patients with only one or no BBS mutation were further investigated by single nucleotide polymorphism (SNP) analysis. In total, mutations were detected in 44 patients. Twenty percent had two mutations in BBS1, 18% in BBS2, 4% in BBS9, 43% in BBS10, and 2% in BBS12. Five patients were heterozygous for a sequence variation in BBS6/MKKS. We found eight patients with three sequence variations in two genes, which could be explained by triallelic inheritance, by the prevalence of heterozygous carriers or the third sequence variations representing rare polymorphisms. All changes found in a second BBS gene were amino acid substitutions. Genotype-phenotype correlations suggest a milder phenotype for BBS1 compared to BBS2 and BBS10, which we ascribe to the hypomorphic p.Met390Arg-mutation. Show less

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder that results in retinal degeneration, obesity, cognitive impairment, polydactyly, renal abnormalities, and hypogenitalism. Of the 12 known BBS genes, BBS1 is the most commonly mutated, and a single missense mutation (M390R) accounts for approximately 80% of BBS1 cases. To gain insight into the function of BBS1, we generated a Bbs1(M390R/M390R) knockin mouse model. Mice homozygous for the M390R mutation recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. The obese mutant mice were hyperphagic and hyperleptinemic and exhibited reduced locomotor activity but no elevation in mean arterial blood pressure. Morphological evaluation of Bbs1 mutant brain neuroanatomy revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Similar abnormalities were also observed in the brains of Bbs2(-/-), Bbs4(-/-), and Bbs6(-/-) mice, establishing these neuroanatomical defects as a previously undescribed BBS mouse model phenotype. Ultrastructural examination of the ependymal cell cilia that line the enlarged third ventricle of the Bbs1 mutant brains showed that, whereas the 9 + 2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Together with data from transmission electron microscopy analysis of photoreceptor cell connecting cilia, the Bbs1 M390R mutation does not affect axonemal structure, but it may play a role in the regulation of cilia assembly and/or function. Show less