Presentation on theme: "Sue Griffin, PhD Dillard Professor and Vice Chair Donald W. Reynolds Department of Geriatrics University of Arkansas For Medical Sciences Research Director."— Presentation transcript:
Sue Griffin, PhD Dillard Professor and Vice Chair Donald W. Reynolds Department of Geriatrics University of Arkansas For Medical Sciences Research Director GRECC VAMC Little Rock, Arkansas The Genetics Of Alzheimer’s
Genes are on chromosomes present in the nucleus of every cell
The genetic code has four letters: A=adenine, T=thymine, G=guanine, C=cytosine
Chromosomes in the nucleus The yellow ribbon is held together by A—T and C—G
Chromosomal DNA (genes) carry the code for all proteins necessary to make our body
Facts: A complementary strand (messenger RNA) is made to nuclear DNA—an A on the mRNA is paired with a T on the gene and C with G, over and over to code for the building blocks (amino acids) needed to make every protein! Every amino acid has a unique code
Diversity of Genetic Diseases Simplistic: One gene mutation causes every case. More Complex: Multiple gene mutations cause all cases. Most Complex: Multiple gene mutations cause some cases. Multiple polymorphisms increase risk. Multiple environmental factors increase risk.
What Starts Everything Going Wrong In Alzheimer’s Disease? The genes you inherit (nature) Wear and tear of time (aging) The way you handle your inheritance (nurture)
The -pleated sheet protein -amyloid (A ) This is important!! George Glenner sequenced the protein and Konrad Beyreuther, Dmitry Goldgaber, and St. George-Hyslop and colleagues mapped the A precursor protein ( APP) gene to chromosome 21 What is that sticky insoluble stuff in plaques?
APP is Cleaved to Form -amyloid Functions of APP Responds to injury Membrane Functions Interacts with PS1
Reasoning Behind This Discovery? People with Trisomy 21 have Alzheimer A plaque pathology by middle age (Wisniewski, 1989) Plaques in Down’s as in Alzheimer’s are the product of APP cleavage, so it’s logical that mutations in APP cause the disease in families with lots of Alzheimer’s. Tanzi and others took this candidate gene approach (Plan A in genetic studies). Hypothesis: Fact:
Plan A - Sequence a Specific Gene Studies of Alzheimer families that were based on a pathological characteristic of the disease Because A plaques were the most prominent neuropathological feature, APP was the targeted gene in AD in these families. At least three offending APP mutations in DNA from family members have been identified by searching for mutations by mapping of this gene.
APP Mutations Cause Alzheimer’s Disease.. How did we come to know this??
We thought that we were nearly there! The cause! Yes! But that was only 1989 and...
Then they asked: Do all family members with the mutation have the disease? Yes Do family members who don’t have the mutation have the disease? No (Maybe?) If yes on the first and no on the second = Disease associated, Causative, and Dominant! Family Association Studies
Hmm ~ Why Maybe Not all familial Alzheimer’s disease families have mutations in this gene And all of the known APP mutations taken together don’t account for all of the people (>5%) with familial Alzheimer’s
So Plan B - Mapping Studies - Identified Two Other Causative Genes Taking a more unbiased approach—that is, not looking for a missense sequence in a specific protein—researchers used endonucleases to cleave DNA for restriction fragment length polymorphism (RFLP) studies to identify aberrant cleavage sites. This type of chromosome mapping, identified two more mutated genes (Presenilin-1 and -2) that, like APP mutations, are causative for Alzheimer’s disease.
Restriction endonucleases are enzymes that cleave DNA at specific sites. Absence of a cleavage site can be used to identify a missense or mutated site Notes on RFLP Studies
RFLP mapping of DNA from a case control study identified a chromosome 19 region that associated with, but not causative of, Alzheimer’s disease. The variant was ApoE 4. Plan B Also Identified one of three Apolipoprotein E polymorphisms ( 4) Associated with Increased Alzheimer Risk
Mutations: Several in the APP Gene Presenilin 1 and 2 Genes Copy Number: Polymorphisms: APP e.g. Down’s syndrome Apolipoprotein E Genes Inflammatory Genes
ApoE Facts The ApoE ε4 gene carries a high relative risk: There are three variants— 2, 3, and 4. Inheritance of 4 increases Alzheimer risk 3-9X. More than half of Alzheimer patients have one or more 4 alleles. Inheritance of the 2 allele may be protective. ApoE is important in transport of lipoproteins. But its specific role in neurons is unknown.
These isoforms differ from each other only by single amino acid substitutions at positions 112 and 158 of the 299 amino acid protein but have profound physiological consequences. E2 is uncommon but is associated with both increased and decreased risk for atherosclerosis. Approximately 64 percent of the population carries one or two E3 genes. E3 is the "neutral" Apo E genotype. E4 has been implicated in athero- sclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth. ApoE is a target gene of liver X receptor, a nuclear receptor member that plays a role in metabolic regulation of cholesterol, fatty acid, and glucose homeostasis. Look in Wikipedia Some ApoE 2, 3, and 4 Facts
APP is Cleaved to Form -amyloid Functions of APP: Expression increases in response to injury and in aging Membrane Functions Interacts with PS1
Plaque proximity = less neuronal APP A APP Nuclei
One Important Driver A neuroinflammatory Cytokine named interleukin-1 (IL-1). Why would I say that? What can IL-1 drive?
What Does IL-1 Do? To Neurons Increases production of: i) APP ii) Faulty tau (hyperphosphorylated) iii) Enzymes that breakdown neurotransmitters Decreases production of: i) synaptophysin
Neuro- fibrillary Tangles (red) IL-1 in Microglia (green)
Interleukin-1 has a Sister Cytokine ~ TNF 1.TNF and IL-1 are both elevated in Alzheimer’s disease. 2. They induce each other and act as neuroinflammagens. 3. Both act as gliotransmitters.
Yes Are their heritable variants of the genes that encode these drivers that might increase risk for Alzheimer’s disease? Probably
IL-1 Genotype and Age at Alzheimer’s Onset Factor Odds Ratio ApoE 4 5.5 IL-1A 2,2 4.9 Grimaldi, Griffin, et al. Ann Neurol, 2000
Confirmation of an Old Idea 1.Breitner JC et al Neurology 1994;44:227 2. in ’t Veld BA et al Neurobiol Aging 1998;19:607 3. Zandi PP et al Neurology 2000;54:2066 4. Vlad SC et al Neurology 2008;70:1672 5. Szekely, C. A. Neurology 2008;70:17
Adjusted odds ratios of Alzheimer’s for ibuprofen ( ) and naproxen ( )
Combat Strategies Prevention: Exercise Diet and Stop Smoking Combat Inflammation Treatment: Education and Cognitive Reserve Meds: Aricept, Namenda