IDENTIFICATION OF A SORL1 MUTATION IN A FAMILY WITH ALZHEIMER DISEASE USING WHOLE EXOME SEQUENCING

Abstract

to be due to the extra dosage of the amyloid precursor protein(APP) gene: an established risk factor for AD. Studying mouse models of DS have led to a greater understanding of the significance of trisomy 21 and its relationship with AD. The Tc1 DS mouse carries an almost-complete copy of human chromosome 21 but is not functionally trisomic for APP, an important gene in AD development. The unique genetics of the Tc1 allow the study of the DS phenotype without the effects of APP pathology. Initial characterisation showed abnormalities in cerebellar neuronal density and skull morphology; no additional cerebral defects have since been identified. Cerebral blood flow (CBF) is a key biomarker of tissue vitality and function, and regional hypoperfusion has been observed in AD patients. We used arterial spin labeling (ASL) to image CBF in the Tc1 mouse to investigate the specific effects of chromosome 21 on brain function, without the confounding effects of triplication of the APP gene. Methods: Tc1 mice and wild-type (WT) littermates were imaged in vivo using a 9.4T scanner. Anaesthesia was maintained at 1.25% isoflurane during imaging. A flow-sensitive alternating inversion recovery (FAIR) sequence with a 4-shot segmented spin-echo EPI readout was implemented with parameters: 5 slices, slice thickness1⁄41mm, FOV1⁄420x20mm,matrix size1⁄464x64mm. Results: Figure 1 shows the mean CBF for the Tc1 and control mice within the cortex(A) and hippocampus(B). The Tc1 animals demonstrated a significant decreased in CBF(p<0.05) relative to the control group in both regions. These results may arise for a number of reasons, including the possibility that a neurodegenerative process is occurring. Conclusions: We report a reduction in CBF in the cortex and hippocampus of the Tc1 mouse. Blood flow deficits have previously been reported in clinical DS studies, and attributed to the AD neuropathology seen universally in DS individuals. In the absence of the APP gene, our results suggest that other genes on chromosome 21 may be contributing to the AD-like patterns of hypoperfusion in the Tc1 mouse.