Research

Research on genetic modulation of brain aging and neurodegeneration

The problem of brain aging and neurodegeneration

Methods to better recognize and assess the state of cognitive and other nervous system functions, their changes and possible dysfunction are of utmost importance in modern society. Problems with nervous system function during early development affect childhood and adolescence, but also the successful preservation of cognition in old age is founded in childhood. Another important time point during the life span is around middle age when various risk factors, both neurobiological and vascular, may gradually start to impair nervous system function. Therefore, it would be crucial at this age to be able to better recognize individuals at risk, and unravel strategies to prevent nervous system and vascular function from impairing and to maintain independence in old age. In the elderly, better methods are needed to identify the determinants of both normal age-related changes as well as pathological aberrations, both neurobiological and vascular.

Apolipoprotein E (ApoE) was first identified during 1970s as a serum protein that mediates extracellular cholesterol transport and uptake to the liver. Today ApoE is recognised as a major lipid transport molecule both in the periphery and the central nervous system (CNS). In the periphery most of ApoE is synthesised in the liver, in the CNS most of ApoE is synthesised by glial cells. ApoE does not penetrate the blood-brain-barrier, hence, peripheral ApoE and CNS ApoE are in separate compartments. In the general population 3 common isoforms of ApoE are found (ApoE2, ApoE3, ApoE4) and several clinically important disorders of the vasculature and brain are differentially caused, or modified, by these isoforms of ApoE.

ApoE can be divided into three isoforms on the basis of amino acid polymorphism: E2 (cys 112 , cys 158 ) E3 (cys 112 , arg 158 ) and E4 (arg 112 , arg 158 ) with allele frequencies of 7%, 75% and 18%, respectively, in the Finnish population. It has been previously shown that serum cholesterol levels correlate with ApoE genotype. Serum cholesterol levels increase in the following order E2/E3 < E3/E3 = E2/E4 < E3/E4 < E4/4. Interestingly, a similar hierarchy in ApoE genotypes has been observed in Alzheimer's disease risk, the lowest risk is associated with the E2/E3 and highest risk with the E4/E4 genotype. ApoE has now been recognised to play a role in several pathological processes both in the vasculature and in the CNS.

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ApoE4 is the strongest known genetic risk factor for Alzheimer's disease (Corder et al 1993). However, ApoE4 has been recently implicated in many other behavioral and neuropathological processes as well, suggesting that it mediates certain fundamental developmental or repair mechanisms in the brain. We were among the first to report that ApoE4 is a risk factor for Alzheimer's disease (Czech et al 1993). We have also shown that ApoE4 is associated with a high level of brain beta-amyloid deposition. We have demonstrated unequivocally, by focusing on E3/E3 homozygous subjects, that there is significant allelic variation in the ApoE gene, which modulates brain amyloid deposition and Alzheimer risk, independent of the ApoE isoform (Myllykangas et al 2002, later confirmed in Strandberg et al 2005). This variation is likely to reside in the regulatory regions of the ApoE gene. The study by Myllykangas et al (2002) demonstrates that ApoE3 (which has been widely used as a reference, when assessing the role of E4 and E2 in Alzheimer's disease) can be subdivided into a protective and predisposing E3-haplotypes with respect to Alzheimer's disease risk. This is of considerable interest since half of the people in the world possess the E3/E3 genotype (previously regarded as reference with respect to Alzheimer's diseases).

Studies on genetic modulation of neurodegeration

 

Studies on genetic modulation of neurodegeration have been conducted in collaboration with Finnish neuropathologists and epidemiologists as well as NIH's National Institute of Aging (John Hardy). In addition to the well-known link between Apolipoprotein-E (APOE) e4 allele and Alzheimer's disease, the group has identified certain APOE e3 haplotypes that protect from or predispose to Alzheimer's disease and cortical beta-amyloid deposition. The role of APOE e3 haplotypes in dementia has been subsequently confirmed in a second dataset of elderly Finns. Expression analyses demonstrated that the protective APOE e3 haplotypes exhibit high expression levels in astrocytes and hepatocytes thus linking the expression level of APOE3 to Alzheimer's risk. Studies performed in a large unselected sample of elderly subjects (Vantaa85+ study) have led to the identification of four genetic factors that modulate brain amyloidosis and Alzheimer's disease risk. These are APOE e4 allele, APOE e3-haplotype, Alpha-2-macroglobulin dimorphism, beta-amyloid cleaving enzyme-2 (BACE2) haplotype. In studies of Parkinson's disease rare mutations of the ADH1C and the mitochondrial PolG gene have been found in sporadic Parkinsons's disease, which are probably the first mutations identified in Finnish Parkinson's patients thus far.

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Research on molecular genetics and epidemiology of multiple sclerosis

What is multiple sclerosis?

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and among the commonest causes of neurological disability in young adults. Pathologically, MS is characterized by multiple foci of myelin lesions, which exhibit infiltrates of leukocytes, especially T lymphocytes and microglia/macrophages. These demyelinative lesions impair the function of myelinated axons and lead to a spectrum of neurological symptoms depending on their anatomical location . Most patients present with relapsing-remitting disease, in which there are phases of relapses and complete or near-complete remissions. However, in time neurological disability accumulates and the disease often adopts a secondary progressive course. About 20% of patients do not present with a relapse but exhibit a primarily progressive disease course from onset. There is no curative treatment, but immunomodulatory treatment with beta-interferon, glatiramer acetate (copolymer) and intermittent gammaglobulin has been shown to reduce the number of relapses by 30%.

The etiology of MS is still largely unknown. It is a multifactorial disease with both genetic and environmental contributing factors. The evidence for the role of genetic factors is strong, and is supported at the epidemiological level by twin, half-sibling and adoption studies . MS is considered a polygenic disease, yet no specific susceptibility gene has so far been unequivocally identified. It is believed that environmental, presumably infectious, agents may trigger the disease in genetically susceptible individuals. However, no specific environmental agent has so far been unequivocally implicated. It is believed that several microbial antigens are able to stimulate T-lymphocytes with crossreactivity against myelin proteins.

MS is most common in populations of Northern European descent, especially in Scandinavia , Scotland , Northern states of the USA , and in the southern regions of Canada . In these regions the prevalence of MS is about 100-150/10 5 . Foci of high prevalence have also been found in North-western Sardinia and in certain rural areas of central Europe (e.g. North-western Hungary , Northeast corner of Croatia ). In Finland previous epidemiological surveys have demonstrated three foci with approximately 2-fold increased prevalence as compared to the national average prevalence. In one of these foci (Seinäjoki in Southern Ostrobothnia ) we have recently reported an incidence of 12/10 5 for clinically definite MS, which is the highest incidence ever reported (Sumelahti et al Neuroepidemiology 19: 67-75, 2000 ). Our recent molecular genetic findings suggest that genetic factors play a role in the high incidence and prevalence of MS in this region.

 

Studies on Multiple sclerosis

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Pentti Tienari has been the coordinator in a nation-wide effort, in which more than 1000 MS families have been collected during 1999-2005 for molecular genetic studies. Linkage and association studies in this large familiy material have led to the localisation of seven predisposing genes. These genes are distributed in six distinct chromosomal regions: 2q33, 5p, 6p21.3 (HLA, which harbours at least two predisposing genes), 17q, 18q23 (MBP) and 19q13. In two genomic regions (2q33 and 18q23/MBP) our group is close to identifying the predisposing gene/mutation. A third gene (on 17q22) is close to being identified in a collaboration with prof Leena Peltonen's group (National Public Health Institue, Helsinki ).

By combining epidemiological and molecular genetic approaches the group has demonstrated strong evidence for founder effect in western Finland . Haplotype signatures in western Finnish patients have been identified within the MBP gene and on chromosome 2q33. Some of these haplotype signature have been also found in Swedish and Polish patients indicating distant common ancestor of the patients in these regions. These findings represent the first piece of molecular genetic evidence for founder effect in MS and suggest that genes modulate the geographic distribution of MS more than has been previously appreciated. These findings implicate MBP as an MS susceptiblitity gene and the other gene on 2q33 has been fine mapped on a region less than 500 kb.

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Page updated June 28, 2011
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