Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease
Introduction
Alzheimer disease (AD) is the major and most severe form of dementia in the elderly. Synaptic loss, together with cholinergic deficits, intraneuronal neurofibrillary tangles and extracellular beta-amyloid (Aβ) peptide deposits, are considered the landmarks of AD (Braak and Braak, 1991, DeKosky and Scheff, 1990). Numerous observations have also accumulated suggesting a glutamatergic deficit in the pathophysiologic mechanisms underlying AD (Francis, 2003). Glutamate is the major excitatory neurotransmitter of the brain; in particular, it is the main neurotransmitter of cortical and hippocampal pyramidal neurons and is thus involved in higher mental functions such as cognition, learning and memory. In AD, tau protein hyperphosphorylation, which leads to neurofibrillary tangle formation and amyloid precursor protein conversion to Aβ, occurs mainly in glutamatergic pyramidal cells (Lewis et al., 1987). Consequently, AD is associated with a selective loss of pyramidal neurons and their synapses in the cerebral cortex, leading to cortical atrophy (DeKosky and Scheff, 1990, Francis, 2003, Morrison and Hof, 2002, Pearson et al., 1985). The level of cognitive impairment in AD correlates more strongly with the loss of cortical pyramidal cells than with counts of neurofibrillary tangles or senile plaques or with the level of cholinergic markers in the cerebral cortex (Masliah et al., 1993, Neary et al., 1986, Terry et al., 1991).
In addition to these histopathological findings, numerous biochemical studies also support the notion of altered glutamatergic transmission in AD (Bell et al., 2006, Francis, 2003). The disease is associated with decreased concentration of glutamate in vivo (Antuono et al., 2001, Hattori et al., 2002) as well as in post-mortem brain tissue (Arai et al., 1985). Likewise, glutamate transport both at the plasma membrane and in synaptic vesicles is reduced in the cerebral cortex of AD patients (Hardy et al., 1987, Westphalen et al., 2003). Moreover, the glutamate transporter EAAT1, which is normally found in astrocytes, is atypically expressed by degenerating pyramidal cells in the cortex of AD patients (Scott et al., 2002).
Until recently, research on glutamatergic neurons was hindered by the lack of specific markers. Lately, three vesicular glutamate transporters (VGLUT1-3) have been identified (Fremeau et al., 2004a). These proton-dependent transporters upload glutamate into synaptic vesicles, and despite their distinct and complementary distribution in the central nervous system, share similar biochemical and pharmacologic characteristics (Fremeau et al., 2004a). Vesicular glutamate transporters confer to neurons the capacity to exocytotically release glutamate, and are the first available specific markers of glutamatergic neurons. In the human neocortex, pyramidal neurons express VGLUT1 mRNA in all layers, whereas VGLUT2 transcripts are expressed only in layers II and III (McCullumsmith and Meador-Woodruff, 2003). Thus, both VGLUT1 and VGLUT2-positive terminals account for the flow of information in higher cognitive functions. In contrast, thalamo-cortical terminals, which represent the main sensory afference to the cerebral cortex, express only VGLUT2 (Fujiyama et al., 2001).
In the current study we analyzed VGLUT1 and VGLUT2 expression in the prefrontal cortex of AD patients and controls using subtype specific antiserums. We also examined whether VGLUT1 and VGLUT2 levels were correlated with cognitive deterioration, as assessed by the clinical dementia rating (CDR) scale.
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Human brain samples
Brain samples were obtained from 17 patients and 11 controls from the geriatric department of the Emile Rous Hospital at Limeil-Brévannes, France (Table 1) (Delacourte et al., 1999, Grouselle et al., 1998). Subjects underwent a neuropsychological assessment every 6 months with the Mini-Mental State Examination (Folstein et al., 1975) and the clinical dementia rating (CDR) scale (Hughes et al., 1982) to evaluate their cognitive status. The CDR scores are as follows: 0 = no dementia, 0.5 =
Immunoautoradiography
VGLUT1 and VGLUT2 were first analyzed by immunoautoradiography in the prefrontal cortex (A9) of five matched controls and patients. In both controls and patients, VGLUT1-positive terminals appeared to be homogeneously distributed in the cortex, in agreement with previous studies (Fig. 1 and Alonso-Nanclares and Defelipe, 2005). For the first time, we report the immunodistribution of VGLUT2 in the human cerebral cortex (Fig. 1). Unlike what is seen in rodents (Kaneko et al., 2002), VGLUT2 was
VGLUT1 and VGLUT2 are severely decreased in the prefrontal cortex of AD patients
In the present study, we quantified VGLUT1 and VGLUT2 immunodistribution in the A9 region of the prefrontal cortex from controls and AD patients. Using three different methods (Western blot, immunoautoradiography and immunohistochemistry) we showed a dramatic decline of both vesicular glutamate transporters in the prefrontal cortex of AD patients.
AD is characterized by a progressive and severe decline of cognitive functions whereas sensory-motor functions are affected only at late stages of the
Disclosure statement
The authors declare that they have no actual or potential conflicts of interest.
Acknowledgments
This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération pour la Recherche sur le Cerveau (FRC) and Association France Parkinson. AK and EL were supported by a fellowship from Association France Alzheimer. The authors wish to thank the families who generously donated the brain samples for the present research program.
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