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The dysregulation of glycogen synthase kinase-3 (GSK3) has been implicated in Alzheimer disease (AD) pathogenesis and in Abeta-induced neurotoxicity, leading us to investigate it as a therapeutic target in an intracerebroventricular Abeta infusion model. Infusion of a specific GSK3 inhibitor SB216763 (SB) reduced a downstream target, phospho-glycogen synthase 39%, and increased glycogen levels 44%, suggesting effective inhibition of enzyme activity. Compared to vehicle, Abeta increased GSK3 activity, and was associated with elevations in levels of ptau, caspase-3, the tau kinase phospho-c-jun N-terminal kinase (pJNK), neuronal DNA fragmentation, and gliosis. Co-infusion of SB corrected all responses to Abeta infusion except the induction of gliosis and behavioral deficits in the Morris water maze. Nevertheless, SB alone was associated with induction of neurodegenerative markers and behavioral deficits. These data support a role for GSK3 hyperactivation in AD pathogenesis, but emphasize the importance of developing inhibitors that do not suppress constitutive activity.

Among a variety of neurodegenerative diseases, Alzheimer’s disease (AD) and Huntington’s disease (HD) have been particularly well studied at the genetic and molecular levels. The progressive cognitive decline in AD patients is known to be most closely associated with the pathological signature amyloid-β (Aβ) protein deposited in extracellular plaques and intraneuronal neurofibrillary tangles (NFT) consisting largely of tau protein. AD is heterogeneous and can be caused either by rare autosomal dominant mutations elevating aggregation-prone Aβ or by a mix of environmental and genetic risk factors. In contrast, the sole known genetic cause of HD is mutations of the huntingtin gene that lead to the oligomerization of its gene product (huntingtin) with extra oligoGln (also called polyQ) resulting in neurotoxicity. Loss of synapses and dendritic spines in vulnerable areas are early pathological indices related to cognitive deficits in various neurodegenerative diseases, including AD and HD. Aβ aggregates activate GTPases, RAC and CDC42 via Tiam 1 in a Ca 2+- dependent manner, and these GTPases in turn activate the kinase PAK1, which directly activates LIM kinase (LIMK). LIMK inactivates cofilin and F-actin severing protein, and eventually stimulates actin polymerization, disrupting actin dynamics, which can lead to the formation of actin rods and disruption of dendritic spines. Imbalances in actin dynamics can also occur in other cell types, such as through influencing actomyosin-dependent phagocytosis of neurons by microglia. The SRC family Tyr kinase inhibitor PP2, as well as curcumin, block PAK1 activation in Aβ oligomer-treated neurons. Similarly, in HD models, PAK1 activation enhances polyQ oligomerization and neurotoxicity. We discuss the potential of PAK1 as a viable target for the therapy of both AD and HD.