Moderate Reduction of γ-Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities

Li, Tong; Wen, Hongjin; Brayton, Cory; Laird, Fiona M.; Ma, Guojun; Peng, Shiwen; Placanica, Lisa; Wu, Tingting; Crain, Barbara J.; Price, Donald L.; Eberhart, Charles G.; Wong, Philip C.

doi:10.1523/jneurosci.2152-07.2007

Cited by 77 publications

(69 citation statements)

References 39 publications

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“…Myeloid progenitors are also sensitive to Presenilin dose (Qyang et al 2004), where a multipotent granulocyte/ monocyte progenitor expands in the spleen. Similar dose sensitivity was observed in nicastrin heterozygotes (Li et al 2007). It is possible that in all these cases, a titration mechanism similar to the one described here is in play.…”

Section: Rbp-jksupporting

confidence: 83%

Presenilins, Notch dose control the fate of pancreatic endocrine progenitors during a narrow developmental window

Cras-Méneur¹,

Li²,

Kopan³

et al. 2009

Genes Dev.

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Canonical Notch signaling is thought to control the endocrine/exocrine decision in early pancreatic progenitors. Later, RBP-Jk interacts with Ptf1a and E12 to promote acinar differentiation. To examine the involvement of Notch signaling in selecting specific endocrine lineages, we deregulated this pathway by targeted deletion of presenilin1 and presenilin2, the catalytic core of g-secretase, in Ngn3-or Pax6-expressing endocrine progenitors. Surprisingly, whereas Pax6 + progenitors were irreversibly committed to the endocrine fate, we discovered that Ngn3 + progenitors were bipotential in vivo and in vitro. When presenilin amounts are limiting, Ngn3 + progenitors default to an acinar fate; subsequently, they expand rapidly to form the bulk of the exocrine pancreas. g-Secretase inhibitors confirmed that enzymatic activity was required to block acinar fate selection by Ngn3 progenitors. Genetic interactions identified Notch2 as the substrate, and suggest that g-secretase and Notch2 act in a noncanonical titration mechanism to sequester RBP-Jk away from Ptf1a, thus securing selection of the endocrine fate by Ngn3 progenitors. These results revise the current view of pancreatic cell fate hierarchy, establish that Ngn3 is not in itself sufficient to commit cells to the endocrine fate in the presence of Ptf1a, reveal a noncanonical action for Notch2 protein in endocrine cell fate selection, and demonstrate that acquisition of an endocrine fate by Ngn3 + progenitors is g-secretase-dependent until Pax6 expression begins.[Keywords: Endocrine progenitor; Notch; pancreatic development; Presenilins; cell fate; lineage tracing] Supplemental material is available at http://www.genesdev.org.

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Section: Rbp-jksupporting

confidence: 83%

Presenilins, Notch dose control the fate of pancreatic endocrine progenitors during a narrow developmental window

Cras-Méneur¹,

Li²,

Kopan³

et al. 2009

Genes Dev.

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“…Constitutive as well as conditional knock-out mouse studies have demonstrated that mice with selective ablation of different subunits exhibit different severity of Notch-deficient phenotypes, depending upon the age and subunit targeted (10,41,(55)(56)(57)(58)(59)(60)(61)(62). Hence, these studies suggest that isoform-selective inhibitors offer another avenue for circumventing Notch-related toxicity observed with first generation ␥-secretase inhibitors (11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

Identification of γ-Secretase Inhibitor Potency Determinants on Presenilin

Zhao

Neitzel

et al. 2008

Journal of Biological Chemistry

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Production of amyloid ␤ peptides (A␤), followed by their deposition in the brain as amyloid plaques, contributes to the hallmark pathology of Alzheimer disease. The enzymes responsible for production of A␤, BACE1 and ␥-secretase, are therapeutic targets for treatment of Alzheimer disease. Two presenilin (PS) homologues, referred to as PS1 and PS2, comprise the catalytic core of ␥-secretase. In comparing presenilin selectivity of several classes of ␥-secretase inhibitors, we observed that sulfonamides in general tend to be more selective for inhibition of PS1-comprising ␥-secretase, as exemplified by ELN318463 and BMS299897. We employed a combination of chimeric constructs and point mutants to identify structural determinants for PS1-selective inhibition by ELN318463. Our studies identified amino acid residues Leu 172 , Thr 281 , and Leu 282 in PS1 as necessary for PS1-selective inhibition by ELN318463. These residues also contributed in part to the PS1-selective inhibition by BMS299897. Alanine scanning mutagenesis of areas flanking Leu 172 , Thr 281 , and Leu 282 identified additional amino acids that affect inhibitor potency of not only these sulfonamides but also nonsulfonamide inhibitors, without affecting A␤ production and presenilin endoproteolysis. Interestingly, many of these same residues have been identified previously to be important for ␥-secretase function. These findings implicate TM3 and a second region near the carboxyl terminus of PS1 aminoterminal fragment in mediating the activity of ␥-secretase inhibitors. Our observations demonstrate that PS-selective inhibitors of ␥-secretase are feasible, and such inhibitors may allow differential inhibition of A␤ peptide production and Notch signaling.

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“…Other potential confounders include personality, psychosocial variables, and physical activity. 20,21 Physical activity is protective against cognitive decline and dementia. 18 Outdoor physical activity may lead to increased exposure to ultraviolet radiation, which increases skin cancer risk.…”

mentioning

confidence: 99%

“…The relationship between cancer and AD may reflect differences in DNA methylation, 23 activity of the tumor suppressor gene p53, the enzyme Pin1, or the Wnt signaling pathway. 20 Additionally, NMSC-specific associations with AD can be attributed to mechanisms involving g-secretase signaling 21,24,25 through a Notch 1 signaling pathway. 26,27 This study has a number of limitations.…”

mentioning

confidence: 99%

Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk

et al. 2013

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Objective: To explore the association of nonmelanoma skin cancer (NMSC) and Alzheimer disease (AD) in the Einstein Aging Study, an epidemiologic study of aging in New York City.Methods: Community-residing volunteers aged 70 years or older were assessed annually, followed by multidisciplinary diagnostic consensus. Cancer status and type was obtained by self-report. Cox proportional hazards models were used to test associations between NMSC and subsequent risk of developing a neurocognitive disorder. To deduce a biologically specific association between AD and NMSC, we considered 3 nested outcomes groups: only AD (probable or possible AD as the sole diagnosis), any AD (probable AD or possible AD, as well as mixed AD/ vascular dementia), and all-cause dementia.Results: We followed 1,102 adults with a mean age of 79 years at enrollment. Prevalent NMSC was associated with reduced risk of only AD (hazard ratio 5 0.21; 95% confidence interval 5 0.051-0.87; p 5 0.031) among subjects after adjustment for demographics, hypertension, diabetes, and coronary heart disease. APOE e4 genotypes were available in 769 individuals. The association was similar in magnitude, but nonsignificant, when the number of APOE e4 alleles was included in the model. No significant association was found between NMSC and subsequent development of any AD or all-cause dementia.Conclusions: This population-based longitudinal study shows that individuals older than 70 years with NMSC have a significantly reduced risk of developing AD compared with individuals without NMSC. We deduce Alzheimer-specific neuroprotection, because the effect is attenuated or eliminated when considering less-specific diagnoses such as AD with another diagnosis (any AD) or all-cause dementia. Previous studies observed an inverse relationship between Alzheimer disease (AD) and cancer. The Washington University AD Research Center showed reduced incidence of cancer in participants with prevalent AD, and a nonsignificant trend toward lower incidence of AD in persons with history of cancer at baseline.

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Moderate Reduction of γ-Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities

Cited by 77 publications

References 39 publications

Presenilins, Notch dose control the fate of pancreatic endocrine progenitors during a narrow developmental window

Presenilins, Notch dose control the fate of pancreatic endocrine progenitors during a narrow developmental window

Identification of γ-Secretase Inhibitor Potency Determinants on Presenilin

Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk

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