3 research outputs found
Supplementary Material for: Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease
<p><b><i>Background:</i></b> β-Amyloid (Aβ) is the product of concerted
cleavage of the amyloid precursor protein (APP) by β- and γ-secretases.
However, the molecular mechanisms that regulate this process are not
well understood. Recently, evidence was reported that γ-secretase
activating protein (GSAP, 16 kDa), derived from a larger precursor
protein (98 kDa), plays a role in Aβ metabolism through a mechanism
involving its interaction with both γ-secretase and APP. However, a
detailed evaluation of GSAP protein levels and their association with
clinical and neuropathological variables are lacking during the clinical
progression of Alzheimer disease (AD). <b><i>Methods:</i></b> We
quantified levels of the GSAP precursor (98 kDa) and its active form (16
kDa) in the frontal cortex and hippocampus, areas displaying extensive
Aβ and neurofibrillary tangle (NFT) pathology, in subjects who came to
autopsy with a premortem clinical diagnosis of noncognitive impairment,
mild cognitive impairment, mild to moderate AD, and severe AD using
Western blotting. <b><i>Results:</i></b> Analysis found that 98-kDa GSAP
levels were increased, while those of 16 kDa were reduced in the
frontal cortex of severe-AD subjects. By contrast, GSAP levels remained
stable in the hippocampus. Frontal cortex and hippocampal GSAP 98- and
16-kDa levels were not associated with Aβ, NFT, and neuropathological
criteria across clinical groups. Interestingly, only neocortical 98-kDa
GSAP values showed a significant correlation with the Mini-Mental State
Examination and episodic memory scores. <b><i>Conclusions:</i></b> These
data demonstrate that GSAP proteins are differentially dysregulated in
severe AD, but only the full-length form was associated with cognitive
test scores in AD.</p
PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers
Background: In contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD. Methods: 18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28–56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score. Results: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = −0.21 & −0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = −0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort). Conclusion: This PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder. © 2021 The Author(s)Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]