APOE4 dysregulates autophagy in cultured cells

Human APOE4 (apolipoprotein E4 isoform) is a powerful genetic risk factor for late-onset Alzheimer disease (AD). Many groups have investigated the effect of APOE4 on the degradation of amyloid β (Aβ), the main component of plaques found in the brains of AD patients. However, few studies have focused on the degradation of APOE itself. We investigated the lysosomal trafficking of APOE in cells and found that APOE from the post-Golgi compartment is degraded through an autophagic process requiring the lysosomal membrane protein LAMP2A. We found that APOE4 accumulates in enlarged lysosomes, alters autophagic flux, and changes the proteomic contents of lysosomes following internalization. This dysregulated lysosomal trafficking may represent one of the mechanisms that contributes to AD pathogenesis

Intracranial Arterial Calcifications: Potential Biomarkers of Stroke Risk and Outcome.

Intracranial artery calcifications (IAC), a common and easily identifiable finding on computed tomorgraphy angiography (CTA), has gained recognition as a possible risk factor for ischemic stroke. While atherosclerosis of intracranial arteries is believed to be a mechanism that commonly contributes to ischemic stroke, and coronary artery calcification is well-established as a predictor of both myocardial infarction (MI) and ischemic stroke risk, IAC is not currently used as a prognostic tool for stroke risk or recurrence. This review examines the pathophysiology and prevalence of IAC, and current evidence suggesting that IAC may be a useful tool for prediction of stroke incidence, recurrence, and response to acute ischemic stroke therapy

Cooperation of cell adhesion and autophagy in the brain: Functional roles in development and neurodegenerative disease.

Cellular adhesive connections directed by the extracellular matrix (ECM) and maintenance of cellular homeostasis by autophagy are seemingly disparate functions that are molecularly intertwined, each regulating the other. This is an emerging field in the brain where the interplay between adhesion and autophagy functions at the intersection of neuroprotection and neurodegeneration. The ECM and adhesion proteins regulate autophagic responses to direct protein clearance and guide regenerative programs that go awry in brain disorders. Concomitantly, autophagic flux acts to regulate adhesion dynamics to mediate neurite outgrowth and synaptic plasticity with functional disruption contributed by neurodegenerative disease. This review highlights the cooperative exchange between cellular adhesion and autophagy in the brain during health and disease. As the mechanistic alliance between adhesion and autophagy has been leveraged therapeutically for metastatic disease, understanding overlapping molecular functions that direct the interplay between adhesion and autophagy might uncover therapeutic strategies to correct or compensate for neurodegeneration

Head impacts sustained by male collegiate water polo athletes.

Water polo is a contact sport that is gaining popularity in the United States and carries a risk of repeated head impacts and concussion. The frequency and magnitude of sport-related head impacts have not been described for water polo. We aimed to compare patterns of empirically measured head impact exposure of male collegiate water polo players to patterns previously reported by a survey of current and former water polo athletes. Participants wore water polo caps instrumented with head impact sensors during three seasons of collegiate water polo. Peak linear acceleration (PLA) and peak rotational acceleration (PRA) were recorded for head impacts. Athlete positions were recorded by research staff at the occurrence of each head impact. Head impacts were sustained by athletes in offensive positions more frequently than in defensive and transition positions (246, 59.9% vs. 93, 22.6% vs. 72, 17.5%). 37% of all head impacts during gameplay were sustained by athletes playing the offensive center position. Impact magnitude (means ± SD: PLA = 36.1±12.3g, PRA = 5.0±2.9 krads/sec2) did not differ between position or game scenario. Among goalies, impact frequency and magnitude were similar between games (means ± SD: 0.54±.51 hits/game, PLA = 36.9±14.2g, PRA = 4.3±4.2 krads/sec2) and practices (means ± SD: 0.96±1.11 hits/practice, PLA = 43.7±14.5g, PRA = 3.9±2.5 krads/sec2). We report that collegiate water polo athletes are at risk for sport-related head impacts and impact frequency is dependent on game scenario and player position. In contrast, magnitude does not differ between scenarios or across positions

Head impacts sustained by male collegiate water polo athletes.

Water polo is a contact sport that is gaining popularity in the United States and carries a risk of repeated head impacts and concussion. The frequency and magnitude of sport-related head impacts have not been described for water polo. We aimed to compare patterns of empirically measured head impact exposure of male collegiate water polo players to patterns previously reported by a survey of current and former water polo athletes. Participants wore water polo caps instrumented with head impact sensors during three seasons of collegiate water polo. Peak linear acceleration (PLA) and peak rotational acceleration (PRA) were recorded for head impacts. Athlete positions were recorded by research staff at the occurrence of each head impact. Head impacts were sustained by athletes in offensive positions more frequently than in defensive and transition positions (246, 59.9% vs. 93, 22.6% vs. 72, 17.5%). 37% of all head impacts during gameplay were sustained by athletes playing the offensive center position. Impact magnitude (means ± SD: PLA = 36.1±12.3g, PRA = 5.0±2.9 krads/sec2) did not differ between position or game scenario. Among goalies, impact frequency and magnitude were similar between games (means ± SD: 0.54±.51 hits/game, PLA = 36.9±14.2g, PRA = 4.3±4.2 krads/sec2) and practices (means ± SD: 0.96±1.11 hits/practice, PLA = 43.7±14.5g, PRA = 3.9±2.5 krads/sec2). We report that collegiate water polo athletes are at risk for sport-related head impacts and impact frequency is dependent on game scenario and player position. In contrast, magnitude does not differ between scenarios or across positions

Diminished LC3-Associated Phagocytosis by Huntington's Disease Striatal Astrocytes.

BackgroundIn recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression.ObjectiveThe goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes.MethodsPrimary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells.ResultsAstrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis.ConclusionWe demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes

The Effectiveness of Protective Headgear in Attenuating Ball-to-Forehead Impacts in Water Polo.

Recent reports have demonstrated that there is a serious risk of head impact and injury in water polo. The use of protective headgear in contact sports is a commonly accepted strategy for reducing the risk of head injury, but there are few available protective headgears for use in water polo. Many of those that are available are banned by the sport's governing bodies due to a lack of published data supporting the effectiveness of those headgears in reducing head impact kinematics. To address this gap in knowledge, we launched a water polo ball at the forehead of an anthropomorphic testing device fitted with either a standard water polo headgear or one of two protective headgears. We selected a range of launch speeds representative of those observed across various athlete ages. Mixed-model ANOVAs revealed that, relative to standard headgear, protective headgears reduced peak linear acceleration (by 10.8-21.6%; p < 0.001), and peak rotational acceleration (by 24.5-48.5%; p < 0.001) induced by the simulated ball-to-forehead impacts. We discuss the possibility of using protective headgears in water polo to attenuate head impact kinematics