Abstract
One of the main pathological hallmarks of Alzheimer's disease (AD) is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic) and perisomatic (mostly GABAergic) regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought.
Highlights
Alzheimer’s disease (AD) is the most common form of senile dementia and it is characterized by a progressive loss of memory, coupled with a deterioration of behavioral and cognitive functions
Plaques were observed in all cortical layers and sub-cortical white matter (WM) of the neocortex, as well as in the hippocampal formation and adjacent cortex
Detailed quantitative analyses were performed on tissue from three AD cases (Figures 1–3) and six transgenic mice (Figure 4)
Summary
Alzheimer’s disease (AD) is the most common form of senile dementia and it is characterized by a progressive loss of memory, coupled with a deterioration of behavioral and cognitive functions. Plaques and neurofibrillary tangles are mostly found in the cerebral cortex (entorhinal cortex, hippocampal formation and neocortex), where both their number and the proportion of the cortex affected increases progressively as the disease advances (Braak and Braak, 1991; Dickson, 1997; Thal et al, 2002). These pathological changes can be observed in subcortical structures such as the amygdala, nucleus basalis, thalamus, locus coeruleus and raphe nuclei, during the late stages of AD (e.g., Esiri et al, 1997). It was recently proposed that Aβ oligomers are the main neurotoxins in AD, whose activity is directly linked to tau hyperphosphorylation (De Felice et al, 2008)
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