Alzheimer's disease exists in two forms, early onset familial disease (FAD) and late onset disease. Four million Americans currently suffer from the condition and experts estimate that 22 million people around the world will be so afflicted by 2025. Until recently, researchers had almost no understanding of the disorder's causes and it still lacks preventive or curative therapies. Current therapies focus on compensating for neurotransmitter dysfunction, principally the cholinesterase inhibitors. Priorities are now moving towards the identification of molecules able to prevent beta-amyloid accumulation or new targets for cognitive functions (see for example our current angiotensin report). Furthermore, greater understanding of cognitive processes should also lead to improved treatments for Alzheimer's disease. Repetition in learning is a prerequisite for the formation of accurate and long-lasting memory. Practice is most effective when widely distributed over time, rather than when closely spaced or massed. But even after efficient learning, most memories dissipate with time unless frequently used. Targeting these time-dependent constraints on learning and memory may offer one novel therapeutic approach, however molecular mechanisms underlying this phenomenon are unknown. One target that has received considerable attention due to its proposed involved in Alzheimer's related cognitive dysfunction is protein phosphatase 1 (PP1). The glycogen-associated form of this enzyme derived from skeletal muscle is a heterodimer composed of a 37-kD catalytic subunit and a 124-kD targeting and regulatory subunit, referred to as PP1G. PP1G binds to muscle glycogen with high affinity, thereby enhancing dephosphorylation of glycogen-bound substrates for PP1 such as glycogen synthase and glycogen phosphorylase kinase. Because of these functions, PP1G was postulated to be involved in noninsulin-dependent diabetes mellitus and obesity. One isoform of the regulatory subunit, regulatory subunit 3, has recently been implicated through linkage studies in Alzheimer's disease. Individuals expressing PPP1R3 polymorphisms may suffer an increased risk of developing late onset Alzheimer's disease. There are also reports indicating that PP1 is involved in tau dephosphorylation suggesting that PP1 inhibition may contribute to hyperphosphorylation of tau and formation of AD tangles. Furthermore, PP1 has been linked to the efficacy of learning and memory by limiting acquisition and favoring memory decline. Perhaps Zurich-based researchers who have used a genetic model to demonstrate the role that PP1 plays in this process offer the most convincing evidence. When PP1 is genetically inhibited during learning, short intervals between training episodes are sufficient for optimal performance. The enhanced learning correlates with increased phosphorylation of cyclic AMP-dependent response element binding (CREB) protein, of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and of the GluR1 subunit of the AMPA receptor; it also correlates with CREB-dependent gene expression that, in control mice, occurs only with widely distributed training. Inhibition of PP1 prolongs memory when induced after learning, suggesting that PP1 also promotes forgetting. This property may account for aging-related cognitive decay, as old mutant animals had preserved memory. These findings emphasize the physiological importance of PP1 as a suppresser of learning and memory, and as a potential mediator of cognitive decline during aging and also maybe Alzheimer's disease.

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Entry date October, 2002

Adapted from Genoux et al, Nature 2002 Aug 29;418(6901):970-5