Abstract
The serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) is thought to alter 5-HT signaling and contribute to behavioral and cognitive phenotypes in depression as well as Alzheimer disease (AD). We explored how well the short (S) and long (L) alleles of the 5-HTTLPR align with serotoninergic indices in 60 autopsied cortical samples from early-onset AD/EOAD and late-onset AD/LOAD donors, and age- and sex-matched controls. Stratifying data by either diagnosis-by-genotype or by sex-by-genotype revealed that the donor's 5-HTTLPR genotype, i.e., L/L, S/L, or S/S, did not affect 5-HTT mRNA or protein expression. However, the glycosylation of 5-HTT was significantly higher in control female (vs. male) samples and tended to decrease in female EOAD/LOAD samples, but remained unaltered in male LOAD samples. Glycosylated forms of the vesicular monoamine transporter (VMAT2) were lower in both male and female AD samples, while a sex-by-genotype stratification revealed a loss of VMAT2 glycosylation specifically in females with an L/L genotype. VMAT2 and 5-HTT glycosylation were correlated in male samples and inversely correlated in female samples in both stratification models. The S/S genotype aligned with lower levels of 5-HT turnover in females (but not males) and with an increased glycosylation of the post-synaptic 5-HT2C receptor. Interestingly, the changes in presynaptic glycosylation were evident primarily in female carriers of the APOE ε4 risk factor for AD. Our data do not support an association between 5-HTTLPR genotype and 5-HTT expression, but they do reveal a non-canonical association of 5-HTTLPR genotype with sex-dependent glycosylation changes in pre- and post-synaptic markers of serotoninergic neurons. These patterns of change suggest adaptive responses in 5-HT signaling and could certainly be contributing to the female prevalence in risk for either depression or AD.
Highlights
We examined our samples for 5-HTT mRNA transcript levels based on primer-pairs spanning the acceptor-donor splice sites for Ex3–4, Ex8–9, and Ex12–13. 5-HT transporter (5HTT) mRNA transcript levels [Ex3–4 (P = 0.7020); Ex8–9 (P = 0.1631); Ex12–13 (P = 0.0706)] were not significantly different between controls and a diagnosis of early-onset AD (EOAD) or late-onset/sporadic AD (LOAD). 5-HTT mRNA transcript levels [Ex3–4 (P = 0.7513); Ex8–9 (P = 0.2390); Ex12–13 (P = 0.5263)] were not significantly different between S/S, S/L, and L/L genotypes
Levels of the 80 kDa glycosylated form of 5-HTT were diminished in carriers of the ε4 allele in pooled data [i.e., male + female: P = 0.0404] and this was reflected by a tendency for a loss of glycosylated 5-HTT in female carriers of the ε4 allele [P = 0.0625], but not male carriers [P = 0.3947] (Figure 13)
There was no influence of ε4 status on the glycosylated form of VMAT2 using pooled data [P = 0.3678], but a significant loss of glycosylated VMAT2 was observed in female carriers of the ε4 allele [P = 0.0196], but not male carriers of the allele [P = 0.6029]
Summary
The degeneration of serotoninergic cell bodies in the dorsal raphé nucleus and noradrenergic cell bodies in the locus coeruleus, and their respective ascending projections (Marcyniuk et al, 1986; Zweig et al, 1988; Rub et al, 2000; Parvizi et al, 2001; Grudzien et al, 2007) are acknowledged as critical events in the earliest stages of Alzheimer disease (AD) and likely predispose to a range of physiological and neuropsychiatric sequelae in presymptomatic AD-dementia that potentially are maintained throughout later stages of the disease process. 5-HTTLPR Genotype and Glycosylation loss of glycosylation of VMAT2 (a marker of monoaminergic neurons) concurrent with a relative increase in the glycosylated 5-HT2C receptor (i.e., active, membrane-associated) support the complexity of glycosylation events observed in AD (FrenkelPinter et al, 2017) Some of these glycosylation changes in our sample set are sex-dependent and could be reflecting adaptive responses designed (Heiming and Schaser, 2010) to overcome signaling deficits during the course of the disease
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