Alexia Marriott

Background: During the early stages of Alzheimer’s disease (AD), patients often suffer from prodromal symptoms such as anxiety, impulsivity, depression, agitation, and sleep disturbances prior to the onset of cognitive impairment. Incidentally, the brainstem noradrenergic locus coeruleus (LC) is the first structure to develop hyperphosphorylated ‘pretangle’ tau pathology in the human brain. Furthermore, norepinephrine (NE) influences several physiological processes such as sleep/wake cycle, arousal, stress, mood, and attention which have been implicated in the prodromal behavioral abnormalities. While clinical studies show significant correlations between LC dysfunction and neuropsychiatric symptoms, a causal relationship between early tau accumulation in the LC and the manifestations of prodromal behaviors remains to be resolved. To explore this, we developed a translationally‐relevant tau mouse model that recapitulates the ‘LC first’ phenomena commonly observed in humans.Method: Adult male and female tyrosine hydroxylase (TH)‐Cre mice aged 4 months underwent intra‐LC infusions with a Cre‐dependent adeno‐associated virus (AAV) expressing mCherry, wild‐type (WT) human tau or P301S mutant human tau (n = 3/group). 3 months post‐infusion, mice underwent a panel of behavioral tests to assess sleep latency, locomotor activity, compulsivity, stress‐induced anxiety‐like behavior, association memory deficits, impulsivity, and attentional impairments. Following behavioral tests, brain sections comprising the LC, hippocampus and prefrontal cortex (PFC) were immunostained with TH to assess for LC integrity, AT8 to detect pretangle tau, NE transporter (NET) to evaluate NE fiber intensity in projection regions, and GFAP and IBA1 to identify neuroinflammatory markers. Immunoreactivity (IR) will be calculated as a measure of fluorescence via ImageJ.Result: It has been proposed that tau accumulation in the LC may provoke mild to moderate damage in LC neurons, triggering compensatory mechanisms such as LC hyperactivity. It is hypothesized that at 3 months, LC‐specific tau pathology will result in hyperarousal, compulsivity, anxiety‐like behavior, and impulsivity. In tandem, human tau‐expressing mice are expected to display increased TH, reflecting LC hyperactivity, neuroinflammatory markers and reductions in NE fibers in LC‐projecting regions. These findings will be presented in July 2023.Conclusion: This research will elucidate the role of LC in governing prodromal symptoms. Further studies will be needed to assess molecular mechanisms underlying tau‐mediated LC dysfunction in early AD.

Due to the uncontrollable generators, islanded microgrids powered only by renewable energy require costly energy storage systems. Energy storage needs are amplified when load and generation are misaligned on hourly, monthly, or seasonal timescales. Diversification of both loads and generation can smooth out such mismatches. However, the ideal type of battery to smooth out remaining generation deficits will depend on the duration(s) that energy is stored. This study presents a controls co-design approach to design an islanded microgrid, showing the benefit of hybridizing tidal and solar generation and hybridizing lithium-ion and flow battery energy storage. The optimization of the microgrid’s levelized cost of energy is initially studied in grid-search slices to understand convexity and smoothness. Then, a particle swarm optimization is proposed and used to study the sensitivity of the hybrid system configuration to variations in component costs. The study highlights the benefits of controls co-design, the need to model premature battery failure, and the importance of using battery cost models that are applicable across orders of magnitude variations in energy storage durations. The results indicate that such a hybrid microgrid would currently produce energy at five times the cost of diesel generation, but flow battery innovations could bring this closer to only twice the cost while using 100% renewable energy.