Premium
P3‐391: Detergent‐insoluble glutamate transporters accumulate in both prodromal dementia and late stage Alzheimer's disease
Author(s) -
Cook David G.,
Woltjer Randall L.,
Mookherjee Paramita,
Leverenz James B.,
Montine Thomas J.,
Watson G. Stennis
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1961
Subject(s) - dementia , glutamate receptor , excitatory amino acid transporter , alzheimer's disease , forebrain , formic acid , cerebral cortex , transporter , clinical dementia rating , biochemistry , chemistry , disease , medicine , biology , neuroscience , central nervous system , gene , receptor
the potent GnRHR1 superagonist, leuprolide acetate, halts cognitive decline in female patients with moderate Alzheimer’s disease (AD). Methods: Using extracellular field recordings, we assessed the effect of GnRH1 and leuprolide on the neuronal excitability of hippocampal slices from young and old rats. To further identify mechanisms of GnRH1 action, and having previously determined that GnRHR1 expression is identical in both the AD and age-matched control brain despite the extensive neuronal loss associated with AD, we examined whether GnRH1-signaling supported neurogenesis by assessing the effect of GnRH1 and leuprolide on human embryonic cells (hESC). Results: GnRH1 significantly increased the amplitude of CA1 population spikes in hippocampal slices from old (2.54 0.18 mV to 3.99 0.84 mV, n 3, p 0.05) compared to young (7.0 1.4mV to 7.9 2.7mV, n 5, p 0.548) rats. Importantly, leuprolide acetate also increased neuronal excitability in hippocampal slices from older rats, and displayed a synergistic effect with GnRH1 resulting in the doubling of spike amplitude in old compared to young hippocampal slices. GnRH1 signaling may be an important modulator of impulse transmission in the aging brain which is concomitant with increasing GnRH1 levels with reproductive senescence. GnRH1 (10 nM) treatment for 10 d significantly increased hESC proliferation (34%) and maintained hESC stemness as indicated by the increase in the expression of the pluripotent stem cell marker Oct3/4. Leuprolide acetate (10 nM) also increased cell number (47%) and altered amyloidprecursor protein (A PP) expression. Morphological analysis indicated extensive GnRH1-induced differentiation of hESC. Conclusions: The post-reproductive increase in GnRH1 secretion may therefore induce neurogenesis, markers of which are upregulated in the AD brain. Together, these observations indicate a role for GnRH1 signaling in the aging brain as well as in early embryogenesis, and suggest that there is a recapitulation of the embryonic GnRH-induced signaling events in the aging brain to increase neural transmission.