Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer’s disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting amyloid-beta (Aβ) deposits, tauopathy, and neuroinflammation. Additional studies involving animal models of AD indicate that some AD-related genotypic determinants may be critical factors enhancing temporal and phenotypic symptoms of TBI. Thus in the present study, we examined sub-acute effects of moderate TBI delivered by a gas-driven shock tube device in Aβ depositing Tg2576 mice. Three days later, significant increases in b-amyloid deposition, glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines were observed. Importantly, peripheral treatment with the naturally occurring flavonoid, luteolin, significantly abolished these accelerated pathologies. This study lays the groundwork for a safe and natural compound that could prevent or treat TBI with minimal or no deleterious side effects in combat personnel and others at risk or who have experienced TBI.

Baicalein, a flavonoid isolated from the roots of Scutellaria baicalensis, is known to modulate γ-aminobutyric acid (GABA) type A receptors. Given prior reports demonstrating benefits of GABA_A modulation for Alzheimer's disease (AD) treatment, we wished to determine whether this agent might be beneficial for AD. CHO cells engineered to overexpress wild-type amyloid precursor protein (APP), primary culture neuronal cells from AD mice (Tg2576) and AD mice were treated with baicalein. In the cell cultures, baicalein significantly reduced the production of β-amyloid (Aβ) by increasing APP α-processing. These effects were blocked by the GABA_A antagonist bicuculline. Likewise, AD mice treated daily with i.p. baicalein for 8 weeks showed enhanced APP α-secretase processing, reduced Aβ production, and reduced AD-like pathology together with improved cognitive performance. Our findings suggest that baicalein promotes nonamyloidogenic processing of APP, thereby reducing Aβ production and improving cognitive performance, by activating GABA_A receptors.

We recently found that sAPPα decreases amyloid‐beta generation by directly associating with β‐site amyloid precursor protein (APP)‐converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases glycogen synthase kinase 3 beta (GSK3β)‐mediated Alzheimer's disease (AD)‐like tau phosphorylation in AD patient‐derived neurons, we determined whether sAPPα also reduces GSK3β‐mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3β (Ser9) in primary neurons from sAPPα over‐expressing mice. Further, recombinant human sAPPα evoked the same phenomenon in SH‐SY5Y cells. Further, in SH‐SY5Y cells over‐expressing BACE1, and HeLa cells over‐expressing human tau, sAPPα reduced GSK3β activity and tau phosphorylation. Importantly, the reductions in GSK3β activity and tau phosphorylation elicited by sAPPα were prevented by BACE1 but not γ‐secretase inhibition. In accord, AD mice over‐expressing human sAPPα had less GSK3β activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP β‐processing and GSK3β‐mediated tau phosphorylation and further define the central role of sAPPα in APP autoregulation and AD pathogenesis. image Hypothesized pathway for sAPPα‐mediated reduction of tau phosphorylation: Soluble amyloid precursor protein alpha (sAPPα) increases glycogen synthase kinase 3 beta (GSK3β) inhibitory phosphorylation by inhibiting β‐site APP‐converting enzyme 1 (BACE1) and followed by reduction of tau phosphorylation. BACE1 inhibition also results in a decrease of amyloid‐beta (Aβ) production. We believe these findings might provide a new strategy to use sAPPα, in treating both Aβ and tau pathology.

Adenosine A_2a-receptor activation enhances shortening of isolated cardiomyocytes. In the present study the effect of A_2a-receptor activation on the contractile performance of isolated rat hearts was investigated by recording left ventricular pressure (LVP) and the maximal rate of LVP development (+dP/d t_max). With constant-pressure perfusion, adenosine caused concentration-dependent increases in LVP and +dP/d t_max, with detectable increases of 4.1 and 4.8% at 10⁻⁶M and maximal increases of 12.0 and 11.1% at 10⁻⁴M, respectively. The contractile responses were prevented by the A_2a-receptor antagonists chlorostyryl-caffeine and aminofuryltriazolotriazinyl-aminoethylphenol (ZM-241385) but were not affected by the β₁-adrenergic antagonist atenolol. The adenosine A₁-receptor antagonist dipropylcyclopentylxanthine and pertussis toxin potentiated the positive inotropic effects of adenosine. The A_2a-receptor agonists ethylcarboxamidoadenosine and dimethoxyphenyl-methylphenylethyl-adenosine also enhanced contractility. With constant-flow perfusion, 10⁻⁵M adenosine increased LVP and +dP/d t_maxby 5.5 and 6.0%, respectively. In the presence of the coronary vasodilator hydralazine, adenosine increased LVP and +dP/d t_maxby 7.5 and 7.4%, respectively. Dipropylcyclopentylxanthine potentiated the adenosine contractile responses with constant-flow perfusion in the absence and presence of hydralazine. These increases in contractile performance were also antagonized by chlorostyryl-caffeine and ZM-241385. The results indicate that adenosine increases contractile performance via activation of A_2areceptors in the intact heart independent of β₁-adrenergic receptor activation or changes in coronary flow.