Pathological tau spreads throughout the brain along neuronal connections in Alzheimer's disease (AD), but the mechanisms that underlie this process are poorly understood. Given the high incidence and deleterious consequences of epileptiform activity in AD, we hypothesized neuronal hyperactivity and seizures are key factors in tau spread. To examine these interactions, we created a novel mouse model involving the cross of targeted recombination in active populations (TRAP) mice and the 5 times familial AD (5XFAD; 5X-TRAP) model allowing for the permanent fluorescent labelling of neuronal activity.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
November 1993
Polyamide oligomers, termed peptide nucleic acids (PNAs), bind with high affinity to both DNA and RNA and offer both antisense and antigene approaches for regulating gene expression. When a PNA binds to a complementary sequence in a double-stranded DNA, one strand of the duplex is displaced, and a stable D-loop is formed. Unlike oligodeoxynucleotides for which binding polarity is determined by the deoxyribose sugar, the unrestrained polyamide backbone of the PNA could permit binding to a DNA target in an orientation-independent manner.
View Article and Find Full Text PDFPeptide nucleic acids (PNAs) are polyamide oligomers that can strand invade duplex DNA, causing displacement of one DNA strand and formation of a D-loop. Binding of either a T10 PNA or a mixed sequence 15-mer PNA to the transcribed strand of a G-free transcription cassette caused 90 to 100 percent site-specific termination of pol II transcription elongation. When a T10 PNA was bound on the nontranscribed strand, site-specific inhibition never exceeded 50 percent.
View Article and Find Full Text PDFThe peptides H-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-NH2 (rANF8-15-NH2), Ac-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-NH2 (Ac-rANF8-15-NH2), and their corresponding retro-inverso-isomeric peptides H-D-Ile-D-Arg-D-Asp-D-Ile-D-Arg-Gly-Gly-D-Phe-NH2 (D-rANF15-8-NH2), Ac-D-Ile-D-Arg-D-Asp-D-Ile-D-Arg-Gly-Gly-D-Phe-NH2 (Ac-D-rANF15-8-NH2), were evaluated for their ability to compete for the binding of 125I-rANF5-28 to cultured spontaneously hypertensive rat (SHR) aortic smooth muscle cell membranes. Their stability toward hydrolysis by the neutral endopeptidase thermolysin was also studied. The octapeptides rANF8-15-NH2 and Ac-rANF8-15-NH2 bound with IC50's of 367 pM and 1900 pM, respectively, but were rapidly hydrolyzed by thermolysin.
View Article and Find Full Text PDFInt J Pept Protein Res
July 1988
The synthesis and pharmacological activity of partial retro-inverso modified rat atrial natriuretic factor (rANF) analogs is described. The route to these compounds utilized a combination of solution and solid-phase methods. The analogs prepared all contain a reversed amide bond (psi[NHCO]) at the Ser 25 to Phe26 linkage.
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