P1-075: Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized pathologically by the presence of senile plaques, neurofibrillary tangles and marked neuronal death in the brain of affected patients. Cholinergic neurons originating in basal forebrain nuclei are the most vulnerable targets of degeneration in AD brain. Several lines of transgenic mice have been created to investigate the underlying neurodegenerative mechanisms in AD and to test new therapeutic approaches. Transgenic TgCRND8 mice (Chishti et al., 2001, J. Biol. Chem. 276, 21562) expressing a double mutant form of amyloid precursor protein (APP) have been produced. In 7–month–old TgCRND8 mice, we studied the Aβ deposits–associated neuroinflammation and the number and morphology of the forebrain cholinergic neurons, by means of histochemistry and single and double labelling immunohistochemistry, the extracellular cortical acetylcholine levels in vivo, by means of the microdialysis technique, and the ability to acquire an inhibitory avoidance response in the “step–down” test. Neuronal shrinkage, particularly in correspondence to Aβ(1–42)–immunopositive deposits, and white matter demyelination were widespread in the transgenic mouse brain. In the brain areas where a strong Aβ(1–42) deposition and numerous plaques were detected, reactive microglia and hyperthrophic astrocytes were found infiltrating and surrounding Aβ(1–42)–immunopositive deposits, respectively. A significant reduction in the number of choline acetyltransferase (ChAT)–positive neurons in the nucleus basalis magnocellularis and a decrease of both basal and K+–stimulated extracellular acetylcholine (ACh) levels in the frontal cortex of TgCRND8 mice, respect to non transgenic controls, were found. m2 muscarinic receptor–immunoreactivity was significantly reduced in the primary motor cortex of TgCRND8 mice and no increase in the extracellular ACh levels was brought about by the administration of 0.5 mg/kg i.p. of the muscarinic antagonist scopolamine. A significant cognitive impairment was demonstrated in the step–down test. These findings demonstrate that neuronal damage and cholinergic dysfunction in vivo may underlie the impairment in learning and memory functions in this mouse model of Alzheimer's disease.