Faculty Bibliography

The distribution of heparin binding growth associated molecule (HB-GAM) in the cerebral amyloidoses of Alzheimer's disease (AD) and Down's syndrome (DS), conditions characterized by the deposition of amyloid beta (A beta), was investigated immunohistochemically. Antibodies to HB-GAM, a cytokine which plays an important role in brain development and maturation, showed strong immunoreactivity with senile plaques in both AD and DS. Anti-HB-GAM reacted with pre-amyloid lesions, but only when markers of dystrophic neurites were present. The presence of HB-GAM in AD brains, but not in control brains, was confirmed by Western blotting. We suggest that the presence of HB-GAM in A beta lesions is a marker of neuronal injury

In alzheimer's disease, amyloid beta (A beta) is deposited in senile plaques and amyloid angiopathy. Longer A beta peptides, which extend to residue 42 (A beta 42), have been suggested to be critical for the seeding of amyloid. Aged dogs develop cerebral vessel amyloid and parenchymal preamyloid lesions. Preamyloid in humans is related to senile plaques, whereas in dogs such progression is rare. We evaluated the composition of aged canine vessel amyloid and preamyloid both biochemically and immunohistochemically. The vessel amyloid extended mainly to residue 40 (A beta 40), while preamyloid contained a mixture of A beta 17-42 and A beta 42, with minimal A beta 40. Our results suggest other factors besides A beta 42 are important for neuritic plaque formation

Alzheimer's amyloid beta-protein (A beta) is a modified, pathogenic form of a constitutive host protein, soluble amyloid beta-protein (sA beta). Both are conformational isomers encoded by the gene for the beta-amyloid precursor protein (APP), located on chromosome 21. sA beta and A beta have identical sequence but are thought to differ in their secondary structure and physicochemical properties, hence they are conformational isomers. sA beta is easily degraded, while A beta is particularly resistant. A beta has a high beta-pleated sheet content, while sA beta is thought to be more random-coil and/or alpha-helical. A beta, unlike sA beta, adopts an amyloidogenic conformation, forms aggregates and gives rise to fibrils. Most early-onset forms of Alzheimer's disease (AD) have been linked to mutations of the presenilin 1, presenilin 2 or APP genes, located on chromosomes 14, 1 and 21, respectively. Their relationship to amyloidogenesis is being investigated. On the other hand, the major risk factor for the most common form, sporadic and familial late-onset AD, is the presence of the apoE epsilon 4 allele. Recent studies have shown that a 10 kDa C-terminal fragment of apoE is complexed to A beta in neuritic plaques and that apoE isoforms can modulate amyloid formation in vitro. Moreover, thrombin cleavage of apoE generates a similar C-terminal fragment that can form amyloid-like fibrils. Thus neuritic plaques may contain both A beta and apoE amyloid fibrils. AD can be neuropathologically defined by the presence of several interacting proteins that can adopt an amyloidogenic conformation. This has led us to hypothesize that in AD, amyloidosis may be reactive rather than causative

A significant component of the aging process is genetically determined. Numerous theories of aging exist, many of which postulate the existence of 'longevity genes.' Recent advances in molecular biological and other techniques have allowed a significantly greater understanding of aging and age-related disease. This will be illustrated by four genetic and sporadic diseases: Alzheimer's disease (AD) and related disorders, transthyretin dementia, cerebral amyloid angiopathy-Icelandic type and scrapie related diseases. Alzheimer's disease (AD), the most common of this group, is the leading cause of dementia in Western countries. Recent genetic and biochemical studies have shown the involvement of at least four genes in the pathogenesis of AD. In early-onset familial AD mutations in the beta PP, S182 (presenilin 1) and STM2 (presenilin 2 or E5-1) genes have been found, while in the more common late-onset AD the presence of the apolipoprotein E4 isotype is a major risk factor. Genetic studies have also helped to elucidate the etiology of rarer cerebral amyloidoses such as the recently described Hungarian amyloidosis that is characterized by meningocerebrovascular amyloid deposition, with resultant dementia. This disease is linked to a mutation in the transthyretin gene. It is hoped that in the near future this increase in knowledge will allow the development of therapeutic approaches to slow the aging process