Nowadays an increasing number of scientific papers implicates cholesterol in Alzheimer’s disease (AD)[3WEB+, 4WEB+, 5WEB+]. Directed by the amyloid dogma of AD research these articles discuss an involvement of cholesterol in AD pathogenesis mostly through the modulation of amyloid b protein (Ab) manufacturing and deposition. In our recent contribution we proposed an alternative reasoning that cholesterol homeostasis biological misregulation itself has a key role for synaptic plasticity impairment, neuronal degeneration and is the primary cause for several AD hallmarks not limited to brain amyloid [5WEB+]. We also proposed that the change in Ab neurochemistry in the disease represents physiological mechanism aiming to compensate impaired neural cholesterol dynamics and associated neurotransmission and synaptic plasticity failure [3, 4, 5].
Our recent study demonstrated that rats fed a cholesterol diet possess impaired hippocampal long-term potentiation (LTP), spatial behavior, Alzheimer’s-like brain amyloid and increased neural synthesis of cholesterol and phospholipids [5WEB+, 6]. Acute modulation of cholesterol dynamics (particularly, an increase of cholesterol efflux that models an inability of tissue to redistribute cholesterol and other lipids via lipoprotein (LP) transport) in the hippocampal slices injured both neurotransmission and synaptic plasticity [3, 7], caused disruption of neurofilament and increase of PFH-like tau phosphorylation (reproduced in several studies, see Refs. 3, 5 for citations' details), but preserved the pattern of Ab immunofluorescence .
Except of the above reports [3, 5], there were no other study that would examine interrelation of brain cholesterol turnover and Ab metabolism with respect to synaptic plasticity, deficit which represents the major Alzheimer’s functional abnormality. In the present study we evaluated the effect of Ab on hippocampal LTP and attempted to test its dependency on hippocampal cholesterol synthesis (see Supplement below for additional background information, also see further reading suggestion).