Many potential treatments for Alzheimer's disease target amyloid-beta peptides (Abeta), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Abeta-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Abeta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions.

Many proteins suspected of causing neurodegenerative diseases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid-␤ (A␤) peptides. In vitro, the "Arctic" mutation (A␤E22G) accelerated A␤ fibrillization but decreased the abundance of nonfibrillar A␤ assemblies, compared with wild-type A␤. In human amyloid precursor protein (hAPP) transgenic mice carrying mutations adjacent to A␤ that increase A␤ production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar A␤ assembly (A␤*56). Mice overexpressing Arctic mutant or wildtype A␤ had similar behavioral and neuronal deficits when they were matched for A␤*56 levels but had vastly different plaque loads. Thus, A␤*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar A␤ deposits. Therapeutic interventions that reduce A␤ fibrils at the cost of augmenting nonfibrillar A␤ assemblies could be harmful. Alzheimer disease (AD)3 and many other neurodegenerative disorders are associated with the accumulation of abnormal protein assemblies in the central nervous system (CNS). Much evidence suggests that this association reflects a causal relationship in which the abnormal proteins actually trigger the neuronal dysfunction and degeneration that characterize these conditions (1-3). The prevalence of AD and other neurodegenerative proteinopathies is increasing rapidly around the world, most likely because of their age dependence, the increasing longevity of many populations, and the lack of effective strategies for treatment and prevention (4 -6). This alarming trend underlines the need to better understand the relationship between the accumulation of abnormal proteins in the CNS and the decline of neurological function.This relationship has been difficult to analyze in depth because proteins associated with neurodegenerative disorders can exist in diverse assembly states, and distinct assemblies can differ markedly in pathogenic potential. For example, the amyloid-␤ (A␤) peptide, which seems to play a causal role in AD, can exist as monomers, low molecular weight oligomers (such as dimers and trimers), larger globular oligomers (such as A␤*56, A␤-derived diffusible ligands, amylospheroids, and globulomers), amyloid pores, protofibrils, fibrils, and amyloid plaques that contain densely packed A␤ fibrils and a large number of other molecules and cellular elements (7-15). Which of these structures contributes most critically to neurological decline in AD is a matter of active study and debate that has important implications for therapeutic interventions. Studies of transgenic mice with neuronal expression of human amyloid precursor proteins (hAPP), from which A␤ is released by proteolytic cleavage, suggest that nonfibrillar A␤ assemblies are more critical than amyloid plaques in the pathogene...

Neuronal expression of familial Alzheimer's disease (AD)-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-β (Aβ) peptides causes synaptic dysfunction, inflammation, and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to AD pathogenesis is uncertain. A lipidomics approach to broadly profile fatty acids in brain tissues of hAPP mice revealed an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A2 (GIVA-PLA2). Levels of activated GIVA-PLA2 in the hippocampus were increased in AD patients and hAPP mice. Aβ caused a dose-dependent increase in GIVA-PLA2 phosphorylation in neuronal cultures. Inhibition of GIVA-PLA2 diminished Aβ-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA2 protected hAPP mice against Aβ-dependent deficits in learning and memory, behavioral alterations, and premature mortality. Inhibition of GIVA-PLA2 may be of benefit in the treatment and prevention of AD.