Inhibition of gamma-Secretase Leads to an Increase in Presenilin-1

gamma-Secretase inhibitors (GSIs) are potential therapeutic agents for Alzheimer's disease (AD); however, trials have proven disappointing. We addressed the possibility that gamma-secretase inhibition can provoke a rebound effect, elevating the levels of the catalytic gamma-secretase subunit, presenilin-1 (PS1). Acute treatment of SH-SY5Y cells with the GSI LY-374973 (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, DAPT) augments PS1, in parallel with increases in other gamma-secretase subunits nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1, yet with no increase in messenger RNA expression. Over-expression of the C-terminal fragment (CTF) of APP, C99, also triggered an increase in PS1. Similar increases in PS1 were evident in primary neurons treated repeatedly (4 days) with DAPT or with the GSI BMS-708163 (avagacestat). Likewise, rats examined after 21 days administered with avagacestat (40 mg/kg/day) had more brain PS1. Sustained gamma-secretase inhibition did not exert a long-term effect on PS1 activity, evident through the decrease in CTFs of APP and ApoER2. Prolonged avagacestat treatment of rats produced a subtle impairment in anxiety-like behavior. The rebound increase in PS1 in response to GSIs must be taken into consideration for future drug development.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
Alzheimer's disease
Presenilin-1
gamma-Secretase inhibitor
Therapy
amyloid precursor protein
c-terminal fragment
alzheimers-disease
cerebrospinal-fluid
a-beta
neuropsychiatric symptoms
avagacestat
bms-708163
motor coordination
peptide production
drug development
Neurosciences & Neurology

Garcia-Ayllon, M. S. (author)
Llansola, M. (author)
Felipo, V. (author)
Blennow, Kaj,1958Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology(Swepub:gu)xbleka (author)
Saez-Valero, J. (author)
Göteborgs universitetInstitutionen för neurovetenskap och fysiologi (creator_code:org_t)

In:Molecular Neurobiology: Springer Science and Business Media LLC55:6, s. 5047-50580893-76481559-1182

By the author/editor: Sogorb-Esteve, A ...; Garcia-Ayllon, M ...; Llansola, M.; Felipo, V.; Blennow, Kaj, 19 ...; Saez-Valero, J.

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.