α‐Synuclein staging in the amygdala of a Parkinson's disease model: cell types involved

Abstract

Lewy bodies (ubiquitin and α-synuclein aggregates) can be detected in brain areas in a predictable sequence of six neuropathological stages in Parkinson's disease. Brainstem and olfactory structures are involved in stage 1, whereas the substantia nigra and amygdala are involved in stage 3, prior to cortical spreading. Amygdaloid pathology has been suggested to contribute to non-motor symptoms such as olfactory dysfunction and emotional impairment. This work analysed the distribution of α-synuclein at 16, 30, 43 and 56 weeks in the basolateral, central and cortical amygdaloid complexes of A53T transgenic mice. The expression of calbindin, calretinin and somatostatin was compared in control and transgenic animals. Co-localisation of these markers with α-synuclein was performed. Triple labeling of calbindin, somatostatin and α-synuclein was also investigated. Quantification was carried out using an optical dissector, ImageJ software and confocal microscopy. α-Synuclein-positive cells were mainly concentrated in the basolateral and cortical amygdaloid complexes with a non-significant increase over time from 16 to 30-43 weeks and a significant decrease thereafter. The expression of interneuron markers showed a significant decrease with aging in control animals. When comparing these markers between control and transgenic mice, calretinin was moderately decreased, but calbindin and somatostatin were highly reduced, particularly in the cortical amygdaloid complex. α-Synuclein mostly co-localised with calbindin and a number of these cells also co-expressed somatostatin. These data on α-synucleinopathy staging in the amygdala could help to explain non-motor symptoms as well as to understand the progression of Parkinson's disease in the brain.

Hippocampal α-synuclein and interneurons in Parkinson's disease: Data from human and mouse models

“…We further demonstrated that CB expression decreased with age in all hippocampal regions of control mice, but only in the CA1 region of PD mice. Expression of CB was lower in general in PD mice, in agreement with previous findings in the amygdala . Deficits in CB are associated with impaired spatial learning and long‐term potentiation in mice, and CB overexpression appears to be neuroprotective against PD manifestations .…”

“…This is sufficient for the development of α‐synuclein intracellular aggregates and motor deficits in these mice, similar to those observed in human PD patients . Aggregates of α‐synuclein initially develop in the olfactory bulb, olfactory cortex, and amygdala at 2 months of age and significantly increase at 8 months of age. This correlates with an onset of severe motor manifestations at 8‐9 months of age and deficits in spatial memory, in basal synaptic transmission, in paired‐pulse facilitation, and long‐term depression .…”

“…It is unknown whether this decrease was a result of cell degeneration and apoptosis or autophagy . Our previous results in the amygdala of A53T mice revealed that the total number of cells was maintained over time and the volume was not reduced . In the human amygdala and hippocampus, no significant differences in the number of neurons between control and PD patients have been reported, but significant volume reduction has been described …”

“…). Quantification was performed as described in previous reports and as shown in Figure . For details on quantification procedures used, see Supplementary Material.…”

Response of α-Synuclein Expression to Amyloid β40 and Amyloid β42 administration into Rat Brain

“…Though not many studies have investigated the α-synuclein levels in the amygdala, Flores-Cuadrado et al [23] showed that α-synuclein positive cells are present mostly in the basolateral and cortical amygdala in the A53T transgenic mice, which overexpress α-synuclein. They also showed that there were no increases in the number of α-synuclein positive neurons in the amygdala over 43 weeks between the transgenics and the controls.…”