BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease

Abstractβ-site APP cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for generating pathogenic β-amyloid (Aβ) peptides in Alzheimer's disease (AD). BACE1 knockout mice lack Aβ and are phenotypically normal, suggesting that therapeutic inhibition of BACE1 may be free of mechanism-based side effects. However, direct evidence that BACE1 inhibition would improve cognition is lacking. Here we show that BACE1 null mice engineered to overexpress human APP (BACE1−/−·Tg2576+) are rescued from Aβ-dependent hippocampal memory deficits. Moreover, impaired hippocampal cholinergic regulation of neuronal excitability found in the Tg2576 AD model is ameliorated in BACE1−/−·Tg2576+ bigenic mice. The behavioral and electrophysiological rescue of deficits in BACE1−/−·Tg2576+ mice is correlated with a dramatic reduction of cerebral Aβ40 and Aβ42 levels and occurs before amyloid deposition in Tg2576 mice. Our gene-based approach demonstrates that lower Aβ levels are beneficial for AD-associated memory impairments, validating BACE1 as a therapeutic target for AD

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Alien Registration- Klimko, Joseph (Lewiston, Androscoggin County)

https://digitalmaine.com/alien_docs/27082/thumbnail.jp

Gene inactivations extending reproductive lifespan.

<p>32 gene inactivations extend reproductive lifespan more than 25% in the RNAi hypersensitive strain, <i>nre-1(hd20)lin-15b(hd126)</i> (A). 26 of those gene inactivations also significantly increase reproductive lifespan of wild type (<i>N2</i>) (B). The other six gene inactivations promote reproductive longevity only in the <i>nre-1(hd20)lin-15b(hd126)</i> strains. They may act in neurons or their RNAi inactivations are only effective in the RNAi hypersensitive background. The average of three independent experiments is shown, <i>p<0.05</i> except ^#.</p

Germline genetic inactivations that prolong reproductive lifespan.

<p>In the <i>rrf-1(pk1417)</i> mutant, RNAi predominantly operates in the germline. Ten of the identified genes increase reproductive lifespan when inactivated in the <i>rrf-1</i> mutants. The extension levels are comparable to that in wild type (<i>N2)</i>, except for <i>daf-2</i>, <i>nhx-2</i> and <i>moma-1</i>. The average of three independent experiments is shown, <i>p<0.05</i>.</p

Gene inactivations that promote somatic longevity.

<p>(A–C) RNAi inactivation of <i>daf-2</i>, <i>R07H5.9</i> and <i>C05E11.6</i> decrease RoA by 48%, 15% and 14%, respectively, without a significant effect on IMR. The mean lifespan is significantly increased by 55%, 11% and 10%, respectively (<i>p<0.001</i>). (D and E) Inactivation of <i>nhx-2</i> and <i>sgk-1</i> reduce IMR by 87% and 45%, respectively, but does not significantly affect RoA. The mean lifespan is increased by 30% and 21%, respectively (<i>p<0.001</i>). (F) <i>C44B7.12</i> inactivation reduces IMR by 91%, but increases RoA by 44%. The mean lifespan is not significantly affected. This is one example to represent 20 genes in the Group 3.</p

Reproductive longevity regulatory genes modulate somatic longevity.

<p>(A) The mortality rate curve of the control animals fed with bacteria expressing no dsRNA. The slope of the curve defines the demographic rate of aging (RoA), and the intercept with the y-axis shows initial mortality rate (IMR). (B–D) The effects of the reproductive senescence genes on somatic aging-related parameters, including IMR (B), RoA (C), and mean lifespan (D). Three gene inactivations including <i>daf-2</i>, <i>R07H5.9</i> and <i>C05E11.6</i> (Group 1), reduce RoA without affecting IMR and increase mean lifespan significantly. Inactivation of <i>sgk-1</i> or <i>nhx-2</i> (Group 2), two regulators of sodium reabsorption, reduces IMR with no effect on RoA and extends mean lifespan. There are also 20 other gene inactivations (Group 3) that reduce IMR, but increase RoA and do not alter mean lifespan. Six gene inactivations have no effect on somatic longevity (Group 4). For IMR and RoA, the average with standard deviation of three independent experiments is shown; for mean lifespan extension, three independent experiments were combined for analysis.</p