Download Free Medical Disorders with Complex Genetics - Alzheimers Disease PowerPoint Presentation

Disorders with Complex Genetics - Alzheimers Disease PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical presentation on amyloidosis, which is titled "Disorders with Complex Genetics - Alzheimer’s Disease", to know about the signs and symptoms, causes of Alzheimer’s Disease.

Tags : amyloidosis, Disorders, Complex Genetics, Alzheimers Disease

Published on : May 06, 2021 | Views : 2182 | Downloads : 15

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Disorders with Complex Genetics Alzheimer’s Disease
Slide 2-

Signs & Symptoms: Memory loss for recent events Progresses into dementia  almost total memory loss Inability to converse, loss of language ability Affective/personality disturbance (fatuous, hostile) Death from opportunistic infections, etc. Confirmation of Diagnosis: Neuronal (amyloid, b amyloid, Ab amyloid) plaques Neurofibrillary tangles Brain Atrophy
Slide 3-

Neuronal Plaques in Alzheimer’s Disease From http://www.rnw.nl/health/html/brain.html
Slide 4-

Neurofibrillary Tangles in Alzheimer’s Disease From http://www.rnw.nl/health/html/brain.html
Slide 5-

Plaques and neurofibrillary tangles From Department of Pathology, Virginia Commonwealth University
Slide 6-

http://www.hosppract.com/genetics/9707gen.htm
Slide 7-

http://abdellab.sunderland.ac.uk/lectures/Neurodegeneration/References/Brain_Neurons_AD_Normal.html WRONG! Brain Atrophy in AD
Slide 8-

Classification: (1) FAD v SAD: Familial AD versus Sporadic AD No complete consensus Usually FAD = at least 1 first degree relative affected Sometimes 2 second degree relatives (2) Early v Late Onset: Early onset = usually before 65 Early onset correlated with FAD LOAD = late onset AD
Slide 9-

Breakthrough: (1) Down’s Syndrome Have AD brain pathology in later life Usually, do NOT have AD symptoms (2) Pedigrees with dominant-like transmission: Studied these first Concentrated on chromosome 21
Slide 10-

Alzheimer’s Disease, Type 1: Several mutations in APP gene on chromosome 21 Most common = Val717Iso Produce abnormal beta amyloid fragment 15%-20% of early onset, familial AD Autosomal dominant http://ghr.nlm.nih.gov/condition=alzheimerdisease
Slide 11-

http://perso.wanadoo.fr/alzheimer.lille/APP/APPmutations.html
Slide 12-

Alzheimer’s Disease, Type 3: Mutations (> 130) in the presenilin1 gene on chromosome 14 Most mutations lead to amino acid substitution Overproduction of the beta amyloid fragment 30% - 70% of early onset, familial AD Autosomal dominant
Slide 13-

Alzheimer’s Disease, Type 4: Mutations in the presenilin2 gene on chromosome 1 2 alleles: Asn141Iso and Met239Val Overproduction of the beta amyloid fragment < 5% of early onset, familial AD (only a fewfamilies world wide) Autosomal dominant
Slide 14-

Alzheimer’s Disease, Type 2: Epsilon 4 (e4, AKA E4) allele of the Apolipoprotein E (ApoE) gene on chromosome 19 confers risk Epsilon 2 (e2, AKA E2) allele of the Apolipoprotein E geneon chromosome 19 confers protection Mechanism unclear; ApoE is a very low density lipoprotein that transports cholesterol Most cases are late onset, familial Susceptibility Locus
Slide 15-

Jarvik G, Larson EB, Goddard K, Schellenberg GD, Wijsman EM (1996) Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample. Am J Hum Genet 58:191-200
Slide 16-

http://www.hosppract.com/genetics/9707gen.htm
Slide 17-

Two Major Hypotheses for AD:b amyloid protein (BAP) v. tau BAPtists: The accumulation of a fragment of the amyloid precursor protein or APP (the amyloid beta 42 residue fragment orAb-42) leads to the formation of plaques that someone kill neurons. TAUists: Abnormal phosphorylation of tau proteins makes them “sticky,” leading to the break up of microtubules. The resultingloss of axonal transport causes cell death. (Recently a presenilin hypothesis has been proposed by Shen& Kelleher (2007), PNAS, 104:403-408.)
Slide 18-

Amyloid Hypothesis(it’s the plaques, dummy) The amyloid precursor protein (APP) is broken down by a series of secretases (see next two slides). During this process, a nonsoluble fragment of the APP protein (called Ab-42) accumulates and is deposited outside the cell. The nonsoluble or “sticky” nature of Ab-42 helps other protein fragments(including apoE) to gather into plaques. Somehow the plaques (or possible the migration of Ab-42 outside thecell) cause neuronal death. PSEN1 & PSEN2 genes  subunits of g secretase.
Slide 19-

Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though tobe important for neuronal growth, survival, and repair. From: www.niapublications.org/pubs/unraveling/01.htm
Slide 20-

Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) orAb. From: www.niapublications.org/pubs/unraveling/01.htm
Slide 21-

Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming theplaques seen in the AD brain. From: www.niapublications.org/pubs/unraveling/01.htm
Slide 22-

(1) b-secretase cuts APP protein, giving: b-secretase Pathway: (not drawn to scale)
Slide 23-

Tau Hypothesis(it’s the tangles, dummy) Ordinarily, the t (tau) protein is a microtubule-associated protein thatacts as a three-dimensional “railroad tie” for the microtubule. The microtubule is responsible for axonal transport. Accumulation of phosphate on the tau proteins cause “paired helicalfilaments” or PHFs (like two ropes twisted around each other) that accumulate and lead to the neurofibrillary tangles (NFT). PHFs are themain component in NFTs. Impaired axonal transport is the probable cause of cell death. Focus on MAPT gene (microtubule-associated protein tau) Not in favor anymore.
Slide 24-

Current theory: Multifactorial, involvingseveral pathways. Protein accumulation:  placques & tangles Inflammation: Unregulated activation of glia Lipid distribution: Lipid membrane site of APP cleavage.
Slide 25-

From Sleegers et al. (2010) Trends in Genetics, 26, 84-94, p. 87
Slide 26-

Alzheimers Disease http://www.ambion.com/tools/pathway/pathway.php?pathway=Alzheimer's%20Disease%20Pathway
Slide 27-

Current gene candidates for AD: Changes too rapidly to keep track of. Go to http://Alzgene.org for latest list
Slide 28-

Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins act as “ties” that stabilize the structure of the microtubules. In AD, tau proteins become tangled, unstabilizing the structure of the microtubule. Loss of axonal transport results in cell death.
Slide 29-

AD: The Great Unknown What is causing the majority of AD cases?
Slide 30-

ppt slide no 30 content not found
Slide 31-

HeterogeneityMendelian/Phenocopy Many rare alleles with high penetrance (“Mendelian” forms of the disorder). Almost no person will get two or more of these AD alleles. Non familial cases due to phenocopies.
Slide 32-

Multifactorial Threshold Model Many common alleles with “low” penetrance. Most people will have several risk alleles. Risk alleles are additive (multiplicative). Many additive environmental factors. Genes and environment  liability. Once liability reaches a certain value (i.e., the threshold) a disease process begins.
Slide 33-

HGSS: Carey: Figure 6.1
Slide 34-

Theoretical major causes of AD:
Slide 35-

Mice gratia http://www.kidscolorpages.com/mouse.htm Human APPgene Human ApoEgene Human Presenilingene Animal Models
Slide 36-

Figure 1. Development of the Transgenic Mouse Model of Alzheimer's Disease. The transgene consists of the human APP gene containing a mutation causing a rare form of early-onset familial Alzheimer's disease (Val717Phe). The transgene, whose expression is driven by the platelet-derived growth factor (PDGF) promoter, is microinjected into mouse eggs and implanted in a pseudopregnant female mouse. After the progeny are screened for the presence of the transgene, they are bred and their offspring are analyzed for pathologic features characteristic of Alzheimer's disease. The brains of the transgenic PDAPP (PDGF promoter expressing amyloid precursor protein) mice have abundant -amyloid deposits (made up of the A peptide), dystrophic neurites, activated glia, and overall decreases in synaptic density. From NEJM Volume 332:1512-1513
Slide 37-

From McGowan, Erikson & Hutton (2006), Trend in Genetics, 22: 281-289.