title: Neuropathological and biochemical assessments of an Alzheimer's disease patient treated with the γ-secretase inhibitor semagacestat.
abstract: Amyloid deposition has been implicated as the key determinant of Alzheimer's disease (AD) pathogenesis. Interventions to antagonize amyloid accumulation and mitigate dementia are now under active investigation. We conducted a combined clinical, biochemical and neuropathological assessment of a participant in a clinical trial of the γ-secretase inhibitor, semagacestat. This patient received a daily oral dose of 140 mg of semagacestat for approximately 76 weeks. Levels of brain amyloid-β (Aβ) peptides were quantified using enzyme-linked immunosorbent assays (ELISA). Western blot/scanning densitometry was performed to reveal BACE1, presenilin1, amyloid precursor protein (APP) and its proteolysis-produced C-terminal peptides APP-CT99 and APP-CT83 as well as several γ-secretase substrates. To serve as a frame of reference, the ELISA and Western analyses were performed in parallel on samples from neuropathologically confirmed non-demented control (NDC) and AD subjects who did not receive semagacestat. Neuropathology findings confirmed a diagnosis of AD with frequent amyloid deposits and neurofibrillary tangles in most areas of the cortex and subcortical nuclei as well as cerebellar amyloid plaques. Mean levels of Tris-soluble Aβ40 and glass-distilled formic acid (GDFA)/guanidine hydrochloride (GHCl)-extractable Aβ40 in the frontal lobe and GDFA/GHCl-soluble Aβ40 in the temporal lobe were increased 4.2, 9.5 and 7.7-fold, respectively, in the semagacestat-treated subject compared to those observed in the non-treated AD group. In addition, GDFA/GHCl-extracted Aβ42 was increased 2-fold in the temporal lobe relative to non-treated AD cases. No major changes in APP, β- and γ-secretase and CT99/CT83 were observed between the semagacestat-treated subject compared to either NDC or AD cases. Furthermore, the levels of γ-secretase substrates in the semagacestat-treated subject and the reference groups were also similar. Interestingly, there were significant alterations in the levels of several γ-secretase substrates between the NDC and non-treated AD subjects. This is the first reported case study of an individual enrolled in the semagacestat clinical trial. The subject of this study remained alive for ~7 months after treatment termination, therefore it is difficult to conclude whether the outcomes observed represent a consequence of semagacestat therapy. Additional evaluations of trial participants, including several who expired during the course of treatment, may provide vital clarification regarding the impacts and aftermath of γ-secretase inhibition.
authors: The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Alex E
authors: AE
authors: Roher
authors: The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Chera L
authors: CL
authors: Maarouf
authors: Department of Microbiology, Midwestern University 19555 North 59th Ave., Glendale, AZ 85308.
authors: Tyler A
authors: TA
authors: Kokjohn
authors: The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Charisse M
authors: CM
authors: Whiteside
authors: The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Walter M
authors: WM
authors: Kalback
authors: Laboratory for Neuropathology, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Geidy
authors: G
authors: Serrano
authors: Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Christine
authors: C
authors: Belden
authors: Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Carolyn
authors: C
authors: Liebsack
authors: Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351 ; University of Arizona College of Medicine-Phoenix 550 E. Van Buren St. Phoenix, AZ 85004.
authors: Sandra A
authors: SA
authors: Jacobson
authors: Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Marwan N
authors: MN
authors: Sabbagh
authors: Laboratory for Neuropathology, Banner Sun Health Research Institute 10515 W. Santa Fe Dr., Sun City, AZ 85351.
authors: Thomas G
authors: TG
authors: Beach
keywords: Alzheimer’s clinical trial; Alzheimer’s disease; amyloid-β; semagacestat immunotherapy; γ-secretase; γ-secretase inhibitors; γ-secretase substrates
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