Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid beta protein (A beta) formed by pathological processing of the A beta precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated A beta fragment 25-35 (A beta(25-55)) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled A beta(25-35) peptide was used as negative control. The aggregated forms of A beta peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracere-broventricular injection of A beta(25-35) decreased body weight, induced short- and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, A beta(25-35), the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. In conclusion, the acute intracerebroventricular A beta(25-35) injection induced substantial central modifications in rats, highly reminiscent of the human physiopathology, that could contribute to physiological and cognitive deficits observed in AD. (Am J Pathol 2011, 179:315-334; DO!: 10.1016/j.ajpath.2011.03.021)