A Physiological Role for Amyloid Beta Protein: Enhancement of Learning and Memory

Abstract

Amyloid beta protein (A[beta]) is well recognized as having a significant role in the pathogenesis of Alzheimer's disease (AD). The reason for the presence of A[beta] and its physiological role in non-disease states is not clear. In these studies, low doses of A[beta] enhanced memory retention in two memory tasks and enhanced acetylcholine production in the hippocampus in vivo. We then tested whether endogenous A[beta] has a role in learning and memory in young, cognitively intact mice by blocking endogenous A[beta] in healthy 2-month-old CD-1 mice. Blocking A[beta] with antibody to A[beta] or DFFVG (which blocks A[beta] binding) or decreasing A[beta] expression with an antisense directed at the A[beta] precursor APP all resulted in impaired learning in T-maze foot-shock avoidance. Finally, A[beta]1-42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to A[beta] inhibited hippocampal LTP. These results indicate that in normal healthy young animals the presence of A[beta] is important for learning and memory.

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

“…On the other hand, the amyloidogenic pathway is downregulated during synaptogenesis and we can therefore exclude a pathogenic effect of Ab accumulation (Figure 2). On the contrary, since Ab may stimulate neurotransmission (Morley et al, 2010), lower Ab levels in FXS could exacerbate intellectual deficits.…”

γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

“…Other in vivo studies have shown that intrahippocampal injections of picomolar concentrations of A 1-42 monomers and oligomers to normal mice cause a marked increase of hippocampal LTP and enhancement of reference and contextual memory [95]. More recently, it has been shown that low doses of A enhance memory retention and acetylcholine production in the hippocampus of normal mice [96]. Blocking endogenous A with antibodies or decreasing A expression with antisense directed at APP, all resulted in impaired learning in a spatial memory test [96].…”

The role of inflammatory processes in Alzheimer’s disease

“…Several studies have demonstrated that when otherwise healthy animal models were induced to produce Ab at abnormally low levels, significant deficits in long-term potentiation (LTP), spatial memory, and synaptic plasticity were observed (Morley et al 2010;Puzzo et al 2011). Furthermore, ectopically introduced Ab 1-42 was found to be sufficient to rescue the deficits in LTP only when it was allowed to oligomerize prior to application (Morley et al 2010). Thus, Ab clearly has a complex interaction with the cells of the CNS, and more work is required to characterize precisely what impact different forms and concentrations of this molecule have on cognitive function.…”

“…However, much research has been done in recent years suggesting a physiological role for Ab in memory formation and retention (Morley et al 2010;Puzzo et al 2011;Barbagallo et al 2010). Several studies have demonstrated that when otherwise healthy animal models were induced to produce Ab at abnormally low levels, significant deficits in long-term potentiation (LTP), spatial memory, and synaptic plasticity were observed (Morley et al 2010;Puzzo et al 2011). Furthermore, ectopically introduced Ab 1-42 was found to be sufficient to rescue the deficits in LTP only when it was allowed to oligomerize prior to application (Morley et al 2010).…”