An 8-year-old boy presented to our hospital complaining of a bilateral headache associated with episodes of anterograde amnesia. He had a road traffic accident 3 years ago when a computed tomography (CT) scan revealed traumatic brain injury. In addition, a small pineal cyst (PC) was noted with minor intramural calcifications. A follow-up CT a day later demonstrated increased density in the pineal gland of 60 Hounsfield Units, suggestive of apoplectic changes in the PC. However, the patient was lost to follow-up and presented with memory loss a year and a half later, upon which CT and magnetic resonance imaging revealed enlargement of the PC. PC apoplexy is a very rare occurrence usually affecting young adult women; cases in children are rarely reported. Furthermore, PC apoplexy secondary to severe craniofacial trauma manifesting as memory loss has not yet been reported in the literature to the best of our knowledge.

Aging is by far the most prominent risk factor for Alzheimer\'s disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.

Cerebral amyloid angiopathy (CAA) is a disease in which amyloid β (Aβ) is deposited on the walls of blood vessels in the brain, making those walls brittle and causing cerebral hemorrhage. However, the mechanism underlying its onset is not well understood. The aggregation and accumulation of Aβ cause the occlusion and fragility of blood vessels due to endothelial cell damage, breakdown of the blood-brain barrier, and replacement with elements constituting the blood vessel wall. In this study, we observed the effect of Aβ on human primary brain microvascular endothelial cells (hBMECs) in real-time using quantum dot nanoprobes to elucidate the mechanism of vascular weakening by Aβ. It was observed that Aβ began to aggregate around hBMECs after the start of incubation and that the cells were covered with aggregates. Aβ aggregates firmly anchored the cells on the plate surface, and eventually suppressed cell motility and caused cell death. Furthermore, Aβ aggregation induced the organization of abnormal actin, resulting in a significant increase in intracellular actin dots over 10 μm2. These results suggest that the mechanism by which Aβ forms a fragile vessel wall is as follows: Aβ aggregation around vascular endothelial cells anchors them to the substrate, induces abnormal actin organization, and leads to cell death.

In the future, humans may live in space because of global pollution and weather fluctuations. In microgravity, convection does not occur, which may change the amyloidogenicity of proteins. However, the effect of gravity on amyloid fibril formation is unclear and remains to be elucidated. Here, we analyzed the effect of microgravity on amyloid fibril formation of amyloidogenic proteins including insulin, amyloid β42 (Aβ42), and transthyretin (TTR). We produced microgravity (10-3 g) by using the gravity controller Gravite. Human insulin, Aβ42, and human wild-type TTR (TTRwt) were incubated at pH 3.0, 7.0, and 3.5 at 37 °C, respectively, in 1 g on the ground or in microgravity. We measured amyloidogenicity via the thioflavin T (ThT) method and cell-based 1-fluoro-2,5-bis[(E)-3-carboxy-4-hydroxystyryl]benzene (FSB) assay. ThT fluorescence intensity and cell-based FSB assay results for human insulin samples were decreased in microgravity compared with results in 1 g. Aβ42 samples did not differ in ThT fluorescence intensity in microgravity and in 1 g on the ground. However, in the cell-based FSB assay, the staining intensity was reduced in microgravity compared with that on 1 g. Human TTRwt tended to form fewer amyloid fibrils in ThT fluorescence intensity and cell-based FSB assays in microgravity than in 1 g. Human insulin and Aβ42 showed decreased amyloid fibril formation in microgravity compared with that in 1 g. Human TTRwt tended to form fewer amyloid fibrils in microgravity. Our experiments suggest that the earth\'s gravity may be an accelerating factor for amyloid fibril formation.

Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.