An animal model to test reversal of cognitive decline associated with beta-amyloid pathologies

Abstract

Disposition of beta-amyloid peptide 1–42 (Aβ1–42) in the space around the synapses and formation of Aβ-containing aggregates known as neuritic or senile plaques are hallmark features of neurodegenerative pathologies associated with Alzheimer’s disease (AD). While AD is a multifactorial disease that includes other proteinopathies (e.g., hyperphosphorylated tau aggregates) and neurotransmitter disturbances (e.g., loss of cortical cholinergic innervation), Aβ (soluble or in senile plaques) remains the major undisputed factor that contributes to the pathological and behavior presentation of AD. Overproduction of Aβ and mutations in Aβ precursor (amyloid precursor protein) or enzymes involved in Aβ1–42 production and removal (γ secretase/presenilins) have been shown in cases of early onset of AD and produced AD-like pathologies in animal models. In addition, the level of soluble Aβ1–42 has been shown to correlate with cognitive impairment in animal models before the presence of senile plaques or other histological features of AD. However, much still is unknown about the biochemical processes leading to amyloid formation and its relation to the pathogenesis, neuronal damage/dysfunction, and behavioral changes associated with AD. In this article, we review animal models that have been developed to study AD-like pathologies and then provide detailed methodology to develop an acute rat model of Aβ-induced cognitive impairment. We use this model to examine the cognitive-enhancing effect of novel pharmacological interventions targeting nicotinic acetylcholine receptors.