Heme Deficiency in Alzheimer\u27s Disease: A Possible Connection to Porphyria

Mechanisms that cause Alzheimer\u27s disease (AD), an invariably fatal neurodegenerative disease, are unknown. Important recent data indicate that neuronal heme deficiency may contribute to AD pathogenesis. If true, factors that contribute to the intracellular heme deficiency could potentially alter the course of AD. The porphyrias are metabolic disorders characterized by enzyme deficiencies in the heme biosynthetic pathway. We hypothesize that AD may differ significantly in individuals possessing the genetic trait for an acute hepatic porphyria. We elaborate on this hypothesis and briefly review the characteristics of the acute hepatic porphyrias that may be relevant to AD. We note the proximity of genes encoding enzymes of the heme biosynthesis pathway to genetic loci linked to sporadic, late-onset AD. In addition, we suggest that identification of individuals carrying the genetic trait for acute porphyria may provide a unique resource for investigating AD pathogenesis and inform treatment and management decisions

Heme Deficiency in Alzheimer's Disease: A Possible Connection to Porphyria

Mechanisms that cause Alzheimer's disease (AD), an invariably fatal neurodegenerative disease, are unknown. Important recent data indicate that neuronal heme deficiency may contribute to AD pathogenesis. If true, factors that contribute to the intracellular heme deficiency could potentially alter the course of AD. The porphyrias are metabolic disorders characterized by enzyme deficiencies in the heme biosynthetic pathway. We hypothesize that AD may differ significantly in individuals possessing the genetic trait for an acute hepatic porphyria. We elaborate on this hypothesis and briefly review the characteristics of the acute hepatic porphyrias that may be relevant to AD. We note the proximity of genes encoding enzymes of the heme biosynthesis pathway to genetic loci linked to sporadic, late-onset AD. In addition, we suggest that identification of individuals carrying the genetic trait for acute porphyria may provide a unique resource for investigating AD pathogenesis and inform treatment and management decisions

Universal Rights and Wrongs

This paper argues for the important role of customers as a source of competitive advantage and firm growth, an issue which has been largely neglected in the resource-based view of the firm. It conceptualizes Penrose’s (1959) notion of an ‘inside track’ and illustrates how in-depth knowledge about established customers combines with joint problem-solving activities and the rapid assimilation of new and previously unexploited skills and resources. It is suggested that the inside track represents a distinct and perhaps underestimated way of generating rents and securing long-term growth. This also implies that the sources of sustainable competitive advantage in important respects can be sought in idiosyncratic interfirm relationships rather than within the firm itself

Heme catabolism and heme oxygenase in neurodegenerative disease

Heme oxygenase, the rate-limiting step in heme catabolism, appears to play an important role in a number of neurodegenerative disorders, such as Alzheimer disease. Interestingly, the spatial distribution of heme oxygenase-1 expression in diseased brain is essentially identical to that of the pathological expression of tau, suggesting a key role for both in disease progression. Like heme oxygenase, the expression, phosphorylation, and aggregation of tau are regulated through signal cascades, including the extracellular signal-regulated kinases, whose activities are modulated by oxidative stress. Therefore, the expression of tau and heme oxygenase-1 in a coordinated manner likely plays a pivotal role in the cytoprotection of neuronal cells. This places heme oxygenase at the center of disease pathogenesis and offers a novel therapeutic approach targeted at either the causes or consequences of enzyme induction.Research in the authors’ laboratories is supported by funding from the National Institutes of Health (M.A.S.), the Alzheimer’s Association (M.A.S.), Philip Morris, U.S.A. (G.P.), and the Medical Research Service Department of Veterans Affairs (B.E.D.).Peer reviewe