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• W1998497145 abstract "G-secretase is the complex responsible for the final step in the processing of the amyloid precursor protein (APP), liberating amyloid-b (Ab) peptides of various lengths. Longer Ab species are implicated in the pathological cascade leading to Alzheimer's disease (AD). Presenilin1 (PS1) is the catalytic subunit of the g-secretase complex. More than 160 mutations in PS1 have been linked to familial AD (fAD). We have previously shown that several fAD PS1 mutations lead to a change in PS1 conformation, affect PS1 alignment with the APP substrate, and alter precision of the PS1/g-secretase cleavage site, resulting in increased generation of the Aß42 peptide, the neurotoxic species prone to aggregation. Moreover, using a variety of genetic and pharmacological manipulations we have found that close PS1 N-to C-termini proximity conformation correlates with the increased Ab42/40 ratio, whereas an “open” PS1 conformation (N- and C-termini are far apart) results in the decreased Ab42/40 ratio. Elevated Ab42/40 (total) ratio has also been reported in sporadic AD (sAD) and during normal aging. In addition, Ab imaging of cognitively normal aging adults, combined with postmortem studies, consistently report that ∼20-30% of individuals with no clinical symptoms of dementia show significant Ab deposition in the brain. This suggests that amyloid deposition precedes decline in cognition, and thus, may be the initiator in a cascade of events that lead to structural and functional disruption, and ultimately to age-related memory loss. Therefore, we hypothesize that, similar to genetic mutations in PS1, multiple age-related stress factors shift the PS1 conformation towards “close” PS1 NT-CT proximity, leading to a change in the PS1/g-secretase-substrate cleavage site in a way that favors cleavage of APP at the Aß42 position. We propose that this change in PS1 conformation precedes Aß plaque deposition, and is more pronounced in the vicinity to plaques. Fluorescence lifetime imaging microscopy, (FLIM), a Forster Resonance Energy Transfer (FRET)-based molecular imaging assay, was employed to study PS1 conformation in immunostained human and mouse brain tissue. The PS1 N- and C-termini were detected with epitope-specific antibodies labeled with Alexa488 and Cy3 as a donor- and acceptor-fluorophores, respectively. PS1 conformation was analyzed in neurons within the CA1 hippocampal area. FRET efficiency (EFRET), as a measure of PS1 N- to C-termini proximity was calculated using the following equation: (EFRET%= 100*(t1/donor-t2/acceptor)/t1/donor), where t1=decay lifetime of the Alexa 488 donor fluorophore alone; and t2= donor fluorophore lifetime in the presence of Cy3 acceptor fluorophore (FRET present). FRET efficiency increases, as the donor to acceptor fluorophore distance decreases. To monitor levels of Aß, PS1 and APP, Aß specific ELISA and western blot approaches were used. Human brain tissue samples of non-demented control individuals (n=10, mean age 92.0 ± 10.0 years), as well as AD (n=10, mean age 86.5 ± 9.9 years), and Fronto-temporal Dementia (FTD) (n=5, mean age 71.7 ± 24.8 years) patients were obtained from the Alzheimer Disease Research Center at Massachusetts General Hospital. To investigate the effects of aging on PS1 conformation Tg2576 transgenic mice expressing human sweAPP (Tg (HuAPP695.K670N-M671L)2576) and non-transgenic littermates (Charles River Laboratories) were used for longitudinal studies. Mice were divided into three groups based on pathological characteristics of the Tg2576 mouse model: young animals (1-4 months) with no amyloid deposition and no behavioral anomalies, young adults (7-9 months) with no obvious amyloid deposition but gradual onset of behavioral anomalies, and old animals (17-25 months) with pronounced amyloid deposits and behavioral anomalies. To determine PS1 conformation EFRET was calculated in CA1 hippocampal neurons of sAD and FTD patients, or in age-matching non-dement." @default.
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• W1998497145 date "2011-07-01" @default.
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• W1998497145 title "P3-195: γ-Secretase conformational changes in the Alzheimer's Disease brain" @default.
• W1998497145 doi "https://doi.org/10.1016/j.jalz.2011.05.1636" @default.
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