Perspectives on the Role of APOE4 as a Therapeutic Target for Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease that is coupled with chronic cognitive dysfunction. AD cases are mostly late onset, and genetic risk factors like the Apolipoprotein E (APOE) play a key role in this process. APOE ɛ2, APOE ɛ3, and APOE ɛ4 are three key alleles in the human APOE gene. For late onset, APOE ɛ4 has the most potent risk factor while APOE ɛ2 plays a defensive role. Several studies suggests that APOE ɛ4 causes AD via different processes like neurofibrillary tangle formation by amyloid-β accumulation, exacerbated neuroinflammation, cerebrovascular disease, and synaptic loss. But the pathway is still unclear as to what actions of APOE ɛ4 leads to AD development. Since APOE was found to contribute to many AD pathways, targeting APOE ɛ4 can lead to a hopeful plan of action in development of new drugs to target AD. In this review, we focus on recent studies and perspectives, focusing on APOE ɛ4 as a key molecule in therapeutic strategies.

A neuron, microglia, and astrocyte triple coculture model to study Alzheimer disease

Glial cells are essential to understand Alzheimer disease (AD) progression, given their role in neuroinflammation and neurodegeneration. There is a need for reliable and easy to manipulate models that allow studying the mechanisms behind neuron and glia communication. Currently available models such as co-cultures require complex methodologies and/or might not be affordable for all laboratories. With this in mind, we aimed to establish a straightforward in vitro setting with neurons and glial cells to study AD. We generated a triple co-culture with neurons, microglia and astrocytes. Immunofluorescence, western blot and ELISA techniques were used to characterize the effects of oligomeric Aβ (oAβ) in this model. We found that, in the triple co-culture, microglia increased the expression of anti-inflammatory markers Arginase I and TGF-β1, and reduced pro-inflammatory iNOS and IL-1β, compared with microglia alone. Astrocytes reduced expression of pro-inflammatory A1 markers AMIGO2 and C3, and displayed a ramified morphology resembling physiological conditions. Lastly, neurons increased post-synaptic markers, and developed more and longer branches than in individual primary cultures. Addition of oAβ in the triple co-culture reduced synaptic markers and increased microglial activation, which are hallmarks of AD. Consequently, we developed a reliable model, where cells better resemble physiological conditions: microglia are less inflammatory, astrocytes are less reactive and neurons display a more mature morphology than in individual primary cultures. Moreover, we were able to recapitulate Aβ-induced synaptic loss and inflammation. This model emerges as a powerful tool to study neurodegeneration and inflammation in the context of AD and other neurodegenerative diseases.

A novel Alex3/Gαq protein complex regulating mitochondrial dynamics, dendritic complexity, and neuronal survival

In neurons, mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neuronal activity. Recent studies point to GPCR and G proteins as important regulators of mitochondrial dynamics and energy metabolism. Here we show that activation of Gαq negatively regulates mitochondrial dynamics and trafficking in neurons. Gαq interacts with the mitochondrial trafficking protein Alex3. By generating a CNS-specific armcx3 knock-out mouse line, we demonstrate that Alex3 is required for Gαq effects on mitochondrial dynamics and trafficking, and dendritic growth. Armcx3-deficient mice present decreased OXPHOS complex and ER stress response protein levels, which correlate with increased neuronal death, motor neuron and neuromuscular synaptic loss, and severe motor alterations. Finally, we show that Alex3 disassembles from the Miro1/Gαq complex upon calcium rise. These data uncover a novel Alex3/Gαq complex that regulates neuronal mitochondrial dynamics and neuronal death and allows the control of mitochondrial functions by GPCRs.

Synaptic Loss in Multiple Sclerosis: A Systematic Review of Human Post-mortem Studies

Background: Gray matter pathology plays a central role in the progression of multiple sclerosis (MS). The occurrence of synaptic loss appears to be important but, to date, still poorly investigated aspect of MS pathology. In this systematic review, we drew from the recent knowledge about synaptic loss in human post-mortem studies.Methods: We conducted a systematic search with PubMed to identify relevant publications. Publications available from15 June 2021 were taken into account. We selected human post-mortem studies that quantitatively assessed the synapse number in MS tissue.Results: We identified 14 relevant publications out of which 9 reported synaptic loss in at least one investigated subregion. The most commonly used synaptic marker was synaptophysin; non-etheless, we found substantial differences in the methodology and the selection of reference tissue. Investigated regions included the cortex, the hippocampus, the cerebellum, the thalamus, and the spinal cord.Conclusion: Synaptic loss seems to take place throughout the entire central nervous system. However, the results are inconsistent, probably due to differences in the methodology. Moreover, synaptic loss appears to be a dynamic process, and thus the nature of this pathology might be captured using in vivo synaptic density measurements.

Research Progress on the Role of Inflammatory Mechanisms in the Development of Postoperative Cognitive Dysfunction

Postoperative cognitive dysfunction (POCD), as one of the common postoperative complications, mainly occurs after surgery and anesthesia, especially in the elderly. It refers to cognitive function changes such as decreased learning and memory ability and inability to concentrate. In severe cases, there could be personality changes and a decline in social behavior. At present, a great deal of research had been carried out on POCD, but its specific mechanism remains unclear. The release of peripheral inflammation-related factors, the degradation and destruction of the blood-brain barrier, the occurrence of central inflammation, and the neuronal apoptosis and synaptic loss could be promoted by neuroinflammation indicating that inflammatory mechanisms may play key roles in the occurrence of POCD.

Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimers Disease

Background Synaptic loss and neurite dystrophy are early events in Alzheimers Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo. Methods MRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes. Results The AD patients showed expected relative decreases in regional brain volumes (range, -6 to -23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 x 10-9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD. Conclusions We interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease-associated differences and the feasibility of measuring FISO on commercially available imaging systems makes it a potential surrogate for pathology related to synapse loss that could be used to support early-stage evaluations of novel therapeutics for AD.

Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

Unbiased high-content screening reveals Aβ- and tau-independent synaptotoxic activities in human brain homogenates from Alzheimer’s patients and high-pathology controls

Alzheimer’s disease (AD) is tightly correlated with synapse loss in vulnerable brain regions. It is assumed that specific molecular entities such as Aβ and tau cause synapse loss in AD, yet unbiased screens for synaptotoxic activities have not been performed. Here, we performed size exclusion chromatography on soluble human brain homogenates from AD cases, high pathology non-demented controls, and low pathology age-matched controls using our novel high content primary cultured neuron-based screening assay. Both presynaptic and postsynaptic toxicities were elevated in homogenates from AD cases and high pathology non-demented controls to a similar extent, with more modest synaptotoxic activities in homogenates from low pathology normal controls. Surprisingly, synaptotoxic activities were found in size fractions peaking between the 17–44 kDa size standards that did not match well with Aβ and tau immunoreactive species in these homogenates. The fractions containing previously identified high molecular weight soluble amyloid beta aggregates/”oligomers” were non-toxic in this assay. Furthermore, immunodepletion of Aβ and tau did not reduce synaptotoxic activity. This result contrasts with previous findings involving the same methods applied to 3xTg-AD mouse brain extracts. The nature of the synaptotoxic species has not been identified. Overall, our data indicates one or more potential Aβ and tau independent synaptotoxic activities in human AD brain homogenates. This result aligns well with the key role of synaptic loss in the early cognitive decline and may provide new insight into AD pathophysiology.