Longitudinal brain corticotropin releasing factor and somatostatin in a transgenic mouse (TG2576) model of Alzheimer's disease

Abstract

Neuropeptides corticotropin releasing factor (CRF) and somatostatin (SRIF) are substantially decreased in cortical regions of Alzheimer's disease (AD) post-mortem brain tissue. The accumulation of amyloid-beta (Abeta) in AD brain has been postulated to be neurotoxic. Using male Tg2576 mice transgenic over-expressing amyloid-beta protein precursor (APP), we examined brain concentrations of CRF and SRIF at 12, 18 and 24 months. Mice were evaluated for locomotor activity and spatial memory. The APP mice had continued increased locomotor activity from 6 months of age compared to controls. Spatial memory was impaired beginning at 12 months in the APP mice relative to controls. APP mice at 24 months had a significantly higher number of amyloid plaques when compared to the 12 and 18 month time points. Brain concentrations of SRIF and CRF were significantly altered in a number of cortical and sub-cortical brain regions relative to controls, but in most regions were increased rather than decreased as in clinical AD. This data shows that although the insertion of the APP gene does cause age dependent increase in plaque load, it does not cause a change in regional neuropeptides consistent with AD, suggesting that neuropeptide changes in AD are not solely due to Abeta load.

Fig. 1

Representations of Tissue sections. Photomicrographs of entorhinal cortex sections immunostained for Aβ demonstrating an age-related increase in amyloid deposition. Amyloid plaques appear as oval brown deposits. A – 12 month old APP mouse, B – 12 month old control mouse, C – 18 month old APP mouse, D – 18 month old control mouse, E – 24 month old APP mouse, F – 24 month old control mouse. (Calibration bar: 500 μm).

Fig. 2

(A) CRF measurements in the Entorhinal Cortex (EC) at each time point. All data is expressed as percent control. The dotted line at zero represents the point at which the amount of CRF in the APP would be equal to the control animals. (B) SRIF measurements in the EC at each time point. Significance at individual time points refers to a significant difference between the APP and Control groups at that time point. (p values shown on the graph).

Fig. 3

(A) CRF measurements in the Hypothalamus (HYP) at each time point. (B) SRIF measurements in the HYP at each time point.

Fig. 4

(A) CRF measurements in the Frontal Cortex (FC) at each time point. (B) SRIF measurements in the FC at each time point.

Fig. 5

(A) CRF measurements in the Hippocampus (HIP) at each time point. (B) SRIF measurements in the HIP at each time point.