S2–01–03: Systematic screens identify novel genes for load susceptibility on chromosomes 9 and 10

not available. S2-01-05 FUTURE OF ASSOCIATION STUDIES IN COMMON AD Ulrich Finckh, Laboratoriumsmedizin Dortmund, Dortmund, Germany. Contact e-mail: finckh@labmed.de Background: Only approximately 0.5% of all Alzheimer dementias (AD) are caused by heterozygous mutations in one of several single major genes for autosomal dominant familial AD. Multifactorial etiologies are assumed to underlie all other AD (common AD), including sporadic cases as well as those with positive family history. Twin studies suggest heritabilities between 50 and 80% of common AD. Of the genetic components of common AD, a significant, yet variable and not exactly known fraction (50%?) is attributable to the E4 risk allele of APOE. Meanwhile, genotypes or allele frequencies of over 200 positional or functional candidate genes have been investigated for associations with common AD. However, besides APOE, none of the numerous positive findings in the candidate genes survived replication consistently. Objective(s): To propose criteria for an optimized strategy to investigate candidate genes for common AD. Methods: The PubMed database was searched for genetic association studies on common AD. Conclusions: None of the candidates tested up to now seems to fulfill the three major criteria that are known to be fulfilled by APOE: 1. Evidence of linkage; 2. evidence of functional biochemical involvement; 3. presence of haplotypes with proven functional differences (“isoforms”). Presumably only candidates fulfilling simultaneously these three major criteria are most suitable for future genetic association studies on common AD. S2-01-06 GENETICS & EPIGENETIC STUDIES IN AD Debomoy K. Lahiri, Yuan-Wen Ge, Md Riyaz Basha, Bryan Maloney, De-Mao Chen, Nasser Zawia, Indiana University School of Medicine, Indianapolis, IN, USA; University of Rhode Island, Kingston, RI, USA. Contact e-mail: dlahiri@iupui.edu Background: The amyloid beta-peptide (A ), cleaved from the A -precursor protein (APP) is a leading candidate for the cause of Alzheimer’s disease (AD). Both APP and A appear in healthy individuals. What triggers normal APP and A to be over-expressed and potentially neurotoxic in sporadic cases of AD? Moreover, when and how does this trigger mechanism apply? We have recently characterized two APP gene promoter polymorphisms, which appear to influence the risk of late-onset. Work in the field suggests that the APP gene can be triggered by different agents, including metals, hormones and cytokines. We have recently discovered that developmental exposure of rats to xenobiotic Pb resulted in a delayed (20 months later) over-expression of APP mRNA and an elevation in levels of APP and its amyloidogenic A product. By contrast, APP expression, and APP and A levels, were unaffected when the rats were exposed to Pb in old age. Early developmental Pb exposure induces latent differences in repair of oxidative DNA damage in rat brain. Objective(s): Our hypothesis is that triggering agents (environmental or dietary) operating at a very early stage of development could perturb APP gene regulation via its transcriptional machinery, leading to latent overexpression and subsequent A production. Early studies also suggest APP overexpression in specific areas of the brain in AD patients. Methods: We have utilized cell culture and animal models to study genetic and epigenetic mechanisms at levels of DNA (cloning and transfecion), RNA (Northern, RT/PCR), and protein/ peptides (Western blotting and ELISA). Conclusions: Expression of the APP and BACE genes can be modulated by different chemicals, factors, and free radicals. Characterization of regulatory regions delineates the role of transcriptional factors and response elements in amyloidogenesis. Developmental exposure to Pb elevates A levels in old age via reprogramming of the de novo synthesis of APP, through disturbances of epigenetic pathways such as DNA methylation. Exposure to Pb inhibits the activity of DNA methylases both in vitro and in vivo. These studies are important as they provide a biological mechanism for environmental and other risk factors on the etiology of AD. Supported by NIH grants. MONDAY, JULY 17, 2006 SYMPOSIA S2-02 D&CC (MOLECULAR PATHOLOGY/HISTOPATHOLOGICAL) S2-02-01 A -RELATED CEREBRAL AMYLOID ANGIOPATHY Orso Bugiani, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy. Contact e-mail: bugiani1@virgilio.it Deposition of A in the neuropil and the cerebral vessel walls is a hallmark of both brain aging and Alzheimer’s disease (AD). At the vascular level, A deposition increases the width of the vessel wall and destroys the muscular lamina, while the lumen is reduced. Leptomeningeal and perforating arteries of the cerebral and cerebellar hemispheres are selectively involved. Whether CAA is symptomatic depends on the amount of related lesions, such as multiple cortical and subcortical infarcts, periventricular edema (leukoaraiosis by MRI) due to chronic hypoxia, multiple hematomas in the cerebral cortex, spontaneous relapsing bleeding in the white matter of frontal or temporal lobes, and subarachnoid haemorrhage. Previous bleeding can be recognized by hemosiderin deposits revealed by round shadows in T2*-weighted MRI images. Parenchimal lesions may be responsible for a sudden worsening of cognitive deterioration in AD patients, which occurs after severe headache, fits, and stroke. Such symptoms may affect both patients with the sporadic form of AD and patients with the familial form. Several mutations in the A PP gene (A692G, E693G, D694N, A713T) are associated with familial AD and symptomatic CAA. S24 Symposia S2-02: D&CC (Molecular Pathology/Histopathological)