👤 Klaus Ley

The hallmark lesions of the Alzheimer's disease (AD) brain are amyloid plaques consisting of the β-amyloid protein and neurofibrillary tangles comprised of hyperphosphorylated, aggregated tau protein, which both cause neuronal dysfunction and loss. One goal of neuroprotective therapies is to maintain normal neuronal function and survival in the presence of toxic pathologies such as plaques and tangles. A potential neuroprotective target is nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which regulates the expression of many antioxidant and detoxification genes. Nrf2 mRNA is decreased in AD brains, and deletion of the Nrf2 gene causes increased BACE1 and Aβ production and worsened cognitive deficits in amyloid pathology mouse models. Overexpression of Nrf2 in astrocytes has been shown to be protective against neurodegeneration, but the role of Nrf2 is neurons is unclear. We overexpressed Nrf2 from birth in neurons of 5XFAD amyloid pathology model mice using AAV8, hypothesizing that neuronal Nrf2 overexpression decreases cortical neuron loss and reduces plaque load by decreasing BACE1 levels. We quantified protein levels by immunoblot and neuropathology by immunofluorescent staining, using two-way ANOVA to measure differences between genotypes and AAV treatments. To assess genetic changes, we performed bulk mRNA seq. While neuronal overexpression of Nrf2 in 5XFAD mice did not prevent neuronal loss as measured by NeuN labeling, decrease neuroinflammation by Iba1 or GFAP labeling, or reduce amyloid load by Aβ antibody or methoxy-XO4 staining, we show that increased Nrf2 expression reduces BACE1 protein levels, especially in swollen axonal dystrophic neurites around amyloid plaques. Other proteins that accumulate in dystrophic neurites were also reduced, indicating decreased dystrophic neurites overall. Immunoblot analysis suggested increased autophagy was unlikely to play a role, while bulk mRNA sequencing indicated changes in lipid metabolism and microtubule stability may have contributed to reduced dystrophic neurite formation. Dystrophic neurites impair action potential conductance and contribute to tau seeding and spreading. Their reduction by neuronal Nrf2 overexpression may protect neurons against these pathologic changes. Further study of the mechanisms by which Nrf2 reduces dystrophic neurites may lead to therapeutic strategies that can limit neuritic damage caused by cerebral amyloid accumulation. Show less

Atherosclerosis underlies most coronary artery disease (CAD). It involves a significant autoimmune component against apolipoprotein B (APOB). In this study, we used short activation-induced marker (AIM) assays to characterize APOB-reactive CD4 Show less

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS. A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications. Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HR These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype. Show less

B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase-Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers. Show less