Disorders with Complex Genetics

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

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

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

http://www.hosppract.com/genetics/9707gen.htm

http://abdellab. sunderland. ac http://abdellab.sunderland.ac.uk/lectures/Neurodegeneration/References/Brain_Neurons_AD_Normal.html

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

Following are from the NIA, Alzheimer’s Disease Education and Referral Center, Alzheimer’s Disease: Unraveling the Mystery (www.niapublications.org/ pubs/unraveling/01.htm ff.)

Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though to be important for neuronal growth, survival, and repair.

Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or Ab.

Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming the plaques seen in the AD brain.

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.

Alzheimer’s Disease, Type 1: Several mutations in AAP 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

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

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 few families world wide) Autosomal dominant

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 gene on chromosome 19 confers protection Mechanism unclear; ApoE is a very low density lipoprotein that transports cholesterol Most cases are late onset, familial Susceptibility Locus

Prevalence of APOE genotypes in Alzheimer’s disease (AD) and controls. E2/E2 1.3% 0% E2/E3 12.5% 3.4% E2/E4 4.9% 4.3% E3/E3 59.9% 38.2% E3/E4 20.7% 41.2% E4/E4 0.7% 12.9% 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

http://www.hosppract.com/genetics/9707gen.htm

Animal Models Human APP gene Human ApoE gene Human Presenilin gene Mice gratia http://www.kidscolorpages.com/mouse.htm

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