<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