Familial Alzheimer's Disease Mutations in Presenilins Disrupt Endoplasmic Reticulum Calcium Leak




Nelson, Omar Lloyd

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Alzheimer disease (AD) is the most common form of progressive dementia in adults over the age of 65 years. AD is a fatal brain disease and it currently affects about 27 million people worldwide. It is speculated that the number of people affected by AD will quadruple by 2050. The presence of amyloid beta plaque serves a pathological hallmark for AD, since it was first described by Alois Alzheimer's in 1906. The major risk factors for developing AD are age, mutations in presenilins (PS1 and PS2), mutations in the amyloid precursor protein (APP), cardiovascular diseases, open heart surgery, diabetes, brain injury/head trauma, Apolipoprotein E-e4 (APOE-e4) and the (P86L) mutation in the CALHM1(Calcium homeostasis modulator 1) gene. Multiple missense mutations have been reported in presenilin-1 (PS1), presenilin-2 (PS2) and the amyloid precursor proteins (APP), which are linked to familial AD (FAD). Presenilins are known to function as the catalytic subunit of the (-secretase complex and FAD mutations in presenilins affect APP processing, leading to the accumulation of Aᴲ peptide and amyloid plaque formation in AD brains. In addition to abnormal APP processing, several FAD mutations in presenilins have been linked to abnormal calcium (Ca2+) signaling. Our laboratory recently discovered that presenilin holoproteins function as endoplasmic reticulum (ER) Ca2+ leak channels and that FAD mutations in presenilns affected this function. Our findings potentially provided an explanation for Ca2+ signaling abnormalities resulting from FAD mutations in presenilins. The goal of my thesis project is to establish a connection between presenilins FAD mutations and ER Ca2+ signaling. For these studies we utilized the lipid bilayer reconstitution technique and Ca2+ imaging experiments. In order to establish such a connection I examined the effects of FAD PS1 mutation, FAD PS2 mutation, FAD APP mutation, a mutation in tau and sporadic AD cases on ER Ca2+ leak. In addition, I will map the conductance pore of PS1 using cysteine substitution in transmembrane 6, 7 and 9. These data will help to evaluate the "Ca2+ hypothesis of AD" and will contribute to selecting optimal strategies for treatment of AD.

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