During aging, decreased efficiency of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and autophagic processes in the brain may be a contributing factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Therefore, we analyzed the expression of Bcl-2-associated athanogene 3, a cochaperone that mediates autophagy, and the autophagy adaptors NBR1, NDP52, and sequestosome 1/p62 in the brains of 4-, 8-, and 12-month-old wild-type and Nrf2 knockout (-/-) mice. We also analyzed the levels of total tau and phospho-tau species. There were minimal differences in the expression of autophagy-related genes or tau species in 4-month-old animals; however, by 12 months, all of these autophagy-associated genes were expressed at significantly lower levels in the Nrf2 (-/-) mice. The decreases in the autophagy-associated genes were accompanied by significantly elevated levels of phospho-tau species in the 12-month-old Nrf2 (-/-) brains. These findings indicate that Nrf2 regulation of autophagy-related genes likely plays a greater role in mediating the clearance of tau as an organism ages.

Excitotoxicity was originally postulated to be a late stage side effect of Alzheimer’s disease (AD)-related neurodegeneration, however more recent studies indicate that it may occur early in AD and contribute to the neurodegenerative process. Tau and amyloid beta (Aβ), the main components of neurofibrillary tangles (NFTs) and amyloid plaques, have been implicated in cooperatively and independently facilitating excitotoxicity. Our study investigated the roles of tau and Aβ in AD-related excitotoxicity. In vivo studies showed that tau knockout (tau−/−) mice were significantly protected from seizures and hippocampal superoxide production induced with the glutamate analog, kainic acid (KA). We hypothesized that tau accomplished this by facilitating KA-induced Ca2+ influx into neurons, however lentiviral tau knockdown failed to ameliorate KA-induced Ca2+ influx into primary rat cortical neurons. We further investigated if tau cooperated with Aβ to facilitate KA-induced Ca2+ influx. While Aβ biphasically modulated the KA-induced Ca2+cyt responses, tau knockdown continued to have no effect. Therefore, tau facilitates KA-induced seizures and superoxide production in a manner that does not involve facilitation of Ca2+ influx through KA receptors (KAR). On the other hand, acute pretreatment with Aβ (10 minutes) enhanced KA-induced Ca2+ influx, while chronic Aβ (24 hours) significantly reduced it, regardless of tau knockdown. Given previously published connections between Aβ, group 1 metabotropic glutamate receptors (mGluRs), and KAR regulation, we hypothesized that Aβ modulates KAR via a G-protein coupled receptor pathway mediated by group 1 mGluRs. We found that Aβ did not activate group 1 mGluRs and inhibition of these receptors did not reverse Aβ modulation of KA-induced Ca2+ influx. Therefore, Aβ biphasically regulates KAR via a mechanism that does not involve group 1 mGluR activation.

Alzheimer’s disease (AD) is defined by presence of two pathological hallmarks, the intraneuronal neurofibrillary tangle (NFT) formed by abnormally processed tau, and the extracellular amyloid plaques formed primarily by the amyloid beta peptide (Aβ). In AD it is likely that these two proteins act in concert to impair neuronal function, and there is evidence to suggest that one of the key targets on which they converge is the mitochondria. For example, overexpression of a pathologic form of tau in rat primary cortical neurons exacerbates Aβ-induced mitochondrial membrane potential (ΔΨm) loss due to impairment of the calcium (Ca2+) buffering capability of mitochondria. However the role of physiological levels of tau in mediating Aβ-induced mitochondrial dysfunction was not examined. Therefore in this present study we used primary neurons from wild type (WT) and tau knockout (tau−/−) mice to investigate whether endogenous tau facilitates Aβ–induced ΔΨm loss and alterations in cytosolic calcium (Ca2+cyt). Knocking out tau significantly protected mouse primary cortical neurons from loss of ΔΨm caused by low concentrations of Aβ42, which supports our previous findings. However, the absence of tau resulted in significantly greater increases in Ca2+cyt in response to Aβ treatment when compared to those observed in WT mouse primary cortical neurons. This unexpected outcome may be explained by findings that suggest tau−/− neurons display certain phenotypic abnormalities associated with alterations in Ca2+cyt. Overall, data indicate that tau facilitates Aβ-induced mitochondrial dysfunction and this effect is independent of Aβ-induced alterations in Ca2+cyt.1

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