Molecular basis for amyloid precursor protein mediated neuroprotection in traumatic brain injury
AuthorInampudi, Chaitanya Lakshmi
AffiliationPharmacology and Therapeutics
Document TypePhD thesis
Access StatusOpen Access
© 2019 Dr. Chaitanya Lakshmi Inampudi
Amyloid precursor protein (APP) is neuroprotective in traumatic brain injury (TBI). Treatment with soluble amyloid precursor protein (sAPP) can rescue motor and cognitive deficits following TBI in mouse and rat models (Corrigan et al., 2012c). The neuroprotective active site in sAPP is located in residues 96 to 110 (APP96-110) (Corrigan et al., 2014). We hypothesize that APP96-110 interacts with a specific molecule(s) to trigger its neuroprotective response in TBI. To identify protein(s) interacting with the APP96-110 peptide, a biotin-streptavidin affinity capture method combined with mass spectrometry was utilised. Among the proteins identified, the Amyloid Precursor-like Protein 2 (APLP2) was found to be a robust interacting target for APP96-110. Previous reports showed APLP2 binds to a region in APP which includes 96-110 (Soba et al., 2005). To test the role of APLP2 in TBI, APLP2 wildtype (APLP2+/+) and APLP2 knockout (APLP2-/-) mice, from both sexes, were subjected to mild controlled cortical impact injury. Brains were collected following 7 days of surgery and histopathological assessment was done looking at primary and secondary effects of injury. These include tissue morphology, neuronal loss, axonal injury, tau pathology, astrogliosis and microgliosis. Motor function was assessed by DigiGait over 7 days post-surgery. Initial gait analysis showed the craniotomy procedure itself induced gait disturbances, but to a lesser extent and that injury worsened gait performance in both genotypes. Sex differences were observed in brain injury, with males more susceptible at acute phase of injury with increased motor deficits and astrogliosis in both genotypes. There was greater axonal damage and tau pathology detected in males than females expressing endogenous APLP2. This study highlights the importance of considering craniotomy controls and female and male mice in TBI study. Sex-specific comparisons made between APLP2+/+ and APLP2-/- mice following injury showed the lack of APLP2 in males leads to decreased motor deficits, axonal damage and tau pathology compared to males expressing endogenous APLP2. In the case of females, APLP2-/- mice were less susceptibility to brain injury compared to APLP2+/+ females. This suggests APLP2 expression may be modulated by sex hormones. Using an in silico approach, progesterone and estrogen transcription binding motifs were identified in the mouse and human APLP2 promoter sequence.
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