Genetic aspects of Alzheimer disease Karolina Pesz, Błażej Misiak, Maria M. Sasiadek Department of Genetics Wroclaw Medical University, Poland

Alois Alzheimer (born: 1864, Marktbreit, died: 1915, Wrocław)

Alzheimer disease: early and late onset

Alzheimer disease – etiology

Alzheimer disease molecular pathogenesis

Alzheimer disease - genetics APP PS-1 PS-2 ApoE L2M LRP1 21.q21 (EOAD) 14.q24 (EOAD) 1p4.1 (EOAD) 19q13 (LOAD) 12q13 (LOAD)

Alzheimer disease

This is a rare form of Alzheimer's disease in which people are diagnosed with the disease before age 65. Less than 10% of all Alzheimer's disease patients have this type. Because they experience premature aging, people with Down syndrome are particularly at risk for a form of early onset Alzheimer's disease. Adults with Down syndrome are often in their mid- to late 40s or early 50s when symptoms first appear. Early onset Alzheimer disease

Early onset Alzheimer disease – APP (21q21)

Highlights: ► Presenilin-1 (PS1) is essential for lysosomal acidification and protein degradation ► v-ATPase V0a1 subunit glycosylation and delivery to lysosomes requires PS1 ► PS1 mutations impair lysosomal acidification and protein turnover by autophagy ► Neurons in PS1-deficient mice have lysosomal acidification deficits Early onset Alzheimer disease – presenilin 1 and 2 (14q24; 1p41) Ju-Hyun Lee et al. Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer- Related PS1 Mutations Cell, 141, , 2010

Early onset Alzheimer disease – presenilin 1 and 2 (14q24; 1p41)

Tau protein (17q21) Axonal transport relies on microtubules as tracks, stabilized by the ties of tau protein. Six isoforms of Tau protein, generated through alternative splicing MUTATIONS (exons 2, 3 i 10) tau with altered binding to microtubules, tau agreggations in form of paired helical filaments rapid formation of beta structures AD: neurofibllary tangles are made up of paired helical filaments of 6 hyperphosphorylated isoforms of tau protein.

Tau protein:

Model showing a possible link between axonal transport, microtubules and tau in Alzheimer's disease. Phosphorylation (P) at crucial sites detaches tau from microtubules, leading to the breakdown of microtubules and the accumulation of tau aggregated into paired helical filaments (PHFs).

Tau protein: The 'assembly domain' comprises the C-terminal half; it binds to microtubules and stabilizes them, whereas the N-terminal 'projection domain' protrudes from the microtubule surface. (

Late onset Alzheimer diseasehttp://

Apolipoprotein E

Apolipoprotein E Nature Reviews Neuroscience 1, (2000) J. Herz & U. Beffert

Two studies suggest different theories of how APOE4 (E4) works in Alzheimer's disease (AD), and thus they offer different ways of blocking its action. Normal APOE carries lipids between various cells in the brain. In E4 carriers, the smaller E4 particles compete with full-sized APOE variants [1a], leading to insufficient lipid delivery and higher levels of β-amyloid (Aβ) aggregation. That, in turn, leads to neuronal degeneration [2] and, eventually, to AD [3]. An alternative theory proposed by Mahley et al. postulates that E4 originating from within neurons is proteolytically cleaved into fragments that interfere with mitochondrial activity [1b], leading to neurodegeneration and AD. Other APOE variants are not subject to this proteolytic processing and are thus not toxic. The APOE4 conundrum Osherovich L., SciBX 2(24); 2009

LDL receptor-related protein

Gene dysregulation versus microRNA Maes et al. (2007) - systemic gene deregulation: Expression profiling study: significant changes in gene expression in sporadic AD individuals as compared to aged-matched normal elderly controls. Different groups of genes showed a significant decrease in expression in AD subjects; mainly genes responsible for cytoskeletal maintenance, cellular trafficking and stress response, redox homeostasis, transcription and DNA repair. Moreover some of the deregulated genes are believed to play a role in  -amyloid aggregation and protein tau phosphorylation. Huppi et al. (2007): MicroRNAs may regulate as may as one third to one half of all protein encoding genes. Wang et al. (2008): In early AD the expression of microRNA miR-107 decreases.

Gene dysregulation versus microRNA

Summarizing:

The presentation was prepared, using pictures available on following pages: w.webmd.com/alzheimers/guide/alzheimers- genetichttp:// /medinfo.ufl.edu:8050/year1/humbehav/readingmat/gold- alzheimers_genes.pdfhttp://ki.se/ki/jsp/polopoly.jsp?d=25844&a=8774&l= en&newsdep= px diseasehttp:// alzheimers-disease.1.jpg