Iso-α-Acids, Bitter Components in Beer, Suppress Inflammatory Responses and Attenuate Neural Hyperactivation in the Hippocampus

Due to the growth in aging populations worldwide, prevention and therapy for age-related cognitive decline and dementia are in great demand. We previously demonstrated that long-term intake of iso-α-acids, which are hop-derived bitter compounds found in beer, prevent Alzheimer’s pathology in a rodent model. On the other hand, the effects of iso-α-acids on neural activity in Alzheimer’s disease model mice have not been investigated. Here, we demonstrated that short-term intake of iso-α-acids suppresses inflammation in the hippocampus and improves memory impairment even after disease onset. Importantly, we demonstrated that short-term administration of iso-α-acids attenuated the neural hyperactivation in hippocampus. In 6-month-old 5 × FAD mice exhibiting hippocampus inflammation and memory impairment, oral administration of iso-α-acids for 7 days reduced inflammatory cytokines, including MIP-1α and soluble Aβ and improved object memory in the novel object recognition test. In 12-month-old J20 mice, intake of iso-α-acids for 7 days also suppressed inflammatory cytokines and soluble Aβ in the brain. Manganese-enhanced magnetic resonance imaging (MEMRI) of hippocampi of J20 mice showed increased manganese compared with wild type mice, but iso-α-acids canceled this increased MEMRI signal in J20 mice, particularly in the hippocampus CA1 and CA3 region. Taken together, these findings suggest that short-term intake of iso-α-acids can suppress hippocampus inflammation even after disease onset and improve hyper neural activity in Alzheimer’s disease model mice

Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells

Abstract GM3 synthase (ST3GAL5) is the first biosynthetic enzyme of a-and b-series gangliosides. Patients with GM3 synthase deficiency suffer severe neurological disability and deafness. Eight children (ages 4.1 ± 2.3 years) homozygous for ST3GAL5 c.694C>T had no detectable GM3 (a-series) or GD3 (b-series) in plasma. Their auditory function was characterized by the absence of middle ear muscle reflexes, distortion product otoacoustic emissions and cochlear microphonics, as well as abnormal auditory brainstem responses and cortical auditory-evoked potentials. In St3gal5 −/− mice, stereocilia of outer hair cells showed signs of degeneration as early as postnatal Day 3 (P3); thereafter, blebs devoid of actin or tubulin appeared at the region of vestigial kinocilia, suggesting impaired vesicular trafficking. Stereocilia of St3gal5 −/− inner hair cells were fused by P17, and protein tyrosine phosphatase receptor Q, normally linked to myosin VI at the tapered base of stereocilia, was maldistributed along the cell membrane. B4galnt1 −/− (GM2 synthase-deficient) mice expressing only GM3 and GD3 gangliosides had normal auditory structure and function. Thus, GM3-dependent membrane microdomains might be essential for the proper organization and maintenance of stereocilia in auditory hair cells

Tau Depletion in APP Transgenic Mice Attenuates Task-Related Hyperactivation of the Hippocampus and Differentially Influences Locomotor Activity and Spatial Memory

Hippocampal hyperactivity, ascribed to amyloid β (Aβ)-induced imbalances in neural excitation and inhibition, is found in patients with mild cognitive impairment, a prodromal stage of Alzheimer's disease (AD). To better understand the relationship between hippocampal hyperactivity and the molecular triggers of behavioral impairments in AD, we used Mn-enhanced MRI (MEMRI) to assess neuronal activity after subjecting mice to a task requiring spatial learning and memory. Depletion of endogenous tau in an amyloid precursor protein (APP) transgenic (J20) mouse line was shown to ameliorate hippocampal hyperactivity in J20 animals, tau depletion failed to reverse memory deficits associated with APP/Aβ overproduction. On the other hand, deletion of tau alleviated the hyperlocomotion displayed by APP transgenics, suggesting that the functional effects of Aβ-tau interactions reflect the temporal appearance of these molecules in individual brain areas

Tau Depletion in APP Transgenic Mice Attenuates Task-Related Hyperactivation of the Hippocampus and Differentially Influences Locomotor Activity and Spatial Memory

Hippocampal hyperactivity, ascribed to amyloid beta (A beta)-induced imbalances in neural excitation and inhibition, is found in patients with mild cognitive impairment, a prodromal stage of Alzheimer's disease (AD). To better understand the relationship between hippocampal hyperactivity and the molecular triggers of behavioral impairments in AD, we used Mn-enhanced MRI (MEMRI) to assess neuronal activity after subjecting mice to a task requiring spatial learning and memory. Depletion of endogenous tau in an amyloid precursor protein (APP) transgenic (J20) mouse line was shown to ameliorate hippocampal hyperactivity in J20 animals, tau depletion failed to reverse memory deficits associated with APP/A beta overproduction. On the other hand, deletion of tau alleviated the hyperlocomotion displayed by APP transgenics, suggesting that the functional effects of A beta-tau interactions reflect the temporal appearance of these molecules in individual brain areas

Species-specific roles of sulfolipid metabolism in acclimation of photosynthetic microbes to sulfur-starvation stress

<div><p>Photosynthetic organisms utilize sulfate for the synthesis of sulfur-compounds including proteins and a sulfolipid, sulfoquinovosyl diacylglycerol. Upon ambient deficiency in sulfate, cells of a green alga, <i>Chlamydomonas reinhardtii</i>, degrade the chloroplast membrane sulfolipid to ensure an intracellular-sulfur source for necessary protein synthesis. Here, the effects of sulfate-starvation on the sulfolipid stability were investigated in another green alga, <i>Chlorella kessleri</i>, and two cyanobacteria, <i>Synechocystis</i> sp. PCC 6803 and <i>Synechococcus elongatus</i> PCC 7942. The results showed that sulfolipid degradation was induced only in <i>C</i>. <i>kessleri</i>, raising the possibility that this degradation ability was obtained not by cyanobacteria, but by eukaryotic algae during the evolution of photosynthetic organisms. Meanwhile, <i>Synechococcus</i> disruptants concerning <i>sqdB</i> and <i>sqdX</i> genes, which are involved in successive reactions in the sulfolipid synthesis pathway, were respectively characterized in cellular response to sulfate-starvation. Phycobilisome degradation intrinsic to <i>Synechococcus</i>, but not to <i>Synechocystis</i>, and cell growth under sulfate-starved conditions were repressed in the <i>sqdB</i> and <i>sqdX</i> disruptants, respectively, relative to in the wild type. Their distinct phenotypes, despite the common loss of the sulfolipid, inferred specific roles of <i>sqdB</i> and <i>sqdX</i>. This study demonstrated that sulfolipid metabolism might have been developed to enable species- or cyanobacterial-strain dependent processes for acclimation to sulfate-starvation.</p></div