Alzheimer's disease and Notch signaling

Cleavage of the amyloid precursor protein (APP) by [gamma]-secretase generates a neurotoxic amyloid [beta]-peptide (A[beta]) that is thought to be associated with the neurodegeneration observed in Alzheimer's disease (AD) patients. Presenilin is the catalytic member of the [gamma]-secretase proteolytic complex and mutations in presenilins are the major cause of early-onset familial Alzheimer's disease. In addition to APP, [gamma]-secretase substrates include Notch1 homologues, Notch ligands Delta and Jagged, and additional type I membrane proteins, raising concerns about mechanism-based toxicities that might arise as a consequence of inhibiting [gamma]-secretase. Notch signaling is involved in tumorigenesis as well as in determining the fates of neural and nonneural cells during development and in adults. Alterations in proteolysis of the Notch by [gamma]-secretase could be involved in the pathogenesis of AD. Inconsistently, several recent observations have indicated that enhanced Notch signaling and expression could be instrumental in neurodegeneration in AD. Therefore, detailed and precise study of Notch signaling in AD is important for elucidating diverse mechanisms of pathogenesis and potentially for treating and preventing Alzheimer's disease

Contribution of gamma-secretase to calcium-mediated cell death

Presenilins are the catalytic subunit of the large γ-secretase complex, that promotes intramembranous proteolysis of the beta-amyloid precursor protein (APP), resulting in the production of beta-amyloid (Aβ). Mutant presenilin causes early-onset familial Alzheimer's disease (FAD), is related to abnormal Ca signaling, and render cells vulnerable to cell death. In the present study, we demonstrated that Ca-mediated cell death is functionally associated with γ-secretase activity. We found that γ-secretase activity was elevated during Ca-mediated cell death. Using selective γ-secretase inhibitors, we examined the role of γ-secretase in cell death triggered by increased intracellular Ca. Indeed, treatment with the selective γ-secretase inhibitors, compound E, DAPT, or L-685.458 significantly decreased Ca-triggered cell death with that of the controls, but did not affect staurosporin or tunicamycin-mediated cell death. These results implicate the role of γ-secretase activity in Ca-mediated cell death

Bone mineral density and bone morphology after 5 weeks of treatment in ZDF rats.

<p>(A) Whole body bone mineral density (BMD) after treatments with control, vildagliptin (10mg/kg/day), pioglitazone (30 mg/kg/day), and combination (vidalgliptin 10 mg/kg/day and pioglitazone 30 mg/kg/day), (B) Micro-Computed Tomography (micro-CT) of femur after treatments with control, vildagliptin, pioglitazone, and combination. All data represented as Mean ± SD. *<i>p</i> < 0.05 compared with control group. ^$$<i>p</i> < 0.01 compared with pioglitazone group.</p

Active GLP-1, bone turnover markers (osteocalcin and TRAP 5b), and sclerostin levels in ZDF rats.

<p>(A) serum active GLP-1 levels, (B) serum osteocalcin levels, (C) serum TRAP5b levels, (D) serum sclerostin levels. Blood sampling was done after 5 weeks of treatment with control, vildagliptin (10 mg/kg/day), pioglitazone (30 mg/kg/day) and combination (vildagliptin 10 mg/kg/day and pioglitazone 30 mg/kg/day). And all data represented as Mean ± SD. *<i>p</i> < 0.05 ***, <i>p</i> < 0.001 compared with control group. ^$ <i>p</i> < 0.005, ^$$ <i>p</i> < 0.01, ^$$$ <i>p</i> < 0.0001 versus pioglitazone group.</p

Glucose profile and insulin secretion after 5-week treatment in ZDF rats.

<p>(A) Glucose profile in IPGTT (glucose 2g/kg) before treatment (B) Glucose profile in IPGTT (glucose 2 g/kg) after treatment with control, vildagliptin (10 mg/kg/day), pioglitazone (30 mg/kg/day), and combination (vidalgliptin 10 mg/kg/day and pioglitazone 30 mg/kg/day). (C) AUC of glucose during the IPGTT after treatment (D) serum insulin level at 0 and 15 min in IPGTT after treatment. All data represented as Mean ± SD. **<i>p</i> < 0.01 and ***<i>p</i> < 0.001 (combination group) and ^### <i>p</i> < 0.001 (pioglitazone group) compared with control group. ^$$<i>p</i> < 0.01, ^$$$<i>p</i> < 0.001 compared with control group.</p

Changes in blood glucose level and body weight during the treatment in ZDF rats.

<p>(A) Change in blood glucose level during the treatment with control, vildagliptin (10 mg/kg/day), pioglitazone (30 mg/kg/day), and combination (vidalgliptin 10 mg/kg/day and pioglitazone 30 mg/kg/day), (B) Change in body weight during the treatment with control, vildagliptin, pioglitazone, and combination. All data represented as Mean ± SD. * <i>p</i> < 0.05, ** <i>p</i> < 0.01, *** <i>p</i> < 0.001 (combination group) and ^# <i>p</i> < 0.05, ^## <i>p</i> < 0.01, ^### <i>p</i> < 0.001 (pioglitazone group) compared with control group.</p

Bone histomorphometric results in ZDF rats.

<p>Bone histomorphometric results in ZDF rats.</p