Abstract
Synaptic loss, plaques and neurofibrillary tangles are viewed as hallmarks of Alzheimer’s disease (AD). This study investigated synaptic markers in neocortical Brodmann area 9 (BA9) samples from 171 subjects with and without AD at different levels of cognitive impairment. The expression levels of vesicular glutamate transporters (VGLUT1&2), glutamate uptake site (EAAT2), post-synaptic density protein of 95 kD (PSD95), vesicular GABA/glycine transporter (VIAAT), somatostatin (som), synaptophysin and choline acetyl transferase (ChAT) were evaluated. VGLUT2 and EAAT2 were unaffected by dementia. The VGLUT1, PSD95, VIAAT, som, ChAT and synaptophysin expression levels significantly decreased as dementia progressed. The maximal decrease varied between 12% (synaptophysin) and 42% (som). VGLUT1 was more strongly correlated with dementia than all of the other markers (polyserial correlation = −0.41). Principal component analysis using these markers was unable to differentiate the CDR groups from one another. Therefore, the status of the major synaptic markers in BA9 does not seem to be linked to the cognitive status of AD patients. The findings of this study suggest that the loss of synaptic markers in BA9 is a late event that is only weakly related to AD dementia.
Highlights
Alzheimer’s disease (AD) is characterized by a progressive and severe loss of cognitive abilities
We measured the density of glutamatergic (VGLUT1, VGLUT2, PSD95, and EAAT2), GABAergic (VIAAT and somatostatin) and cholinergic markers, as well as α-tubulin and synaptophysin, in Brodmann area 9 (BA9) samples from 171 individuals stratified according to the clinical dementia rating scale (CDR)
Consistent with previous reports, we found that, with the exception of VGLUT2 and EAAT2, all synaptic markers decreased during the late stages of dementia (CDR5)
Summary
Alzheimer’s disease (AD) is characterized by a progressive and severe loss of cognitive abilities. In neocortical Brodmann area 9 (BA9), the loss of VGLUT1 strongly correlates with cognitive decline[30] These data suggest that the disease progression occurs in two stages. It was recently reported that a massive loss of VGLUT3 (−80%) has only a limited impact on the function of VGLUT3-postive synapses[36] The status of both synaptic and neurotransmission markers in AD, as well as in animal models, has been thoroughly investigated. Recent animal studies revealed the importance of the GABA/glutamate balance in the pathogenesis of AD47–50 These findings implied that to prevent or treat the dementia associated with AD, synaptic functions should be restored. The present study suggests that synaptic loss in BA9 may be involved in the progression of dementia but in a subtler way than previously thought
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