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Amyloid-β plaques and neurofibrillary tau tangles are the neuropathologic hallmarks of Alzheimer's disease (AD), but the spatiotemporal cellular responses and molecular mechanisms underlying AD pathophysiology remain poorly understood. Here we introduce STARmap PLUS to simultaneously map single-cell transcriptional states and disease marker proteins in brain tissues of AD mouse models at subcellular resolution (200 nm). This high-resolution spatial transcriptomics map revealed a core-shell structure where disease-associated microglia (DAM) closely contact amyloid-β plaques, whereas disease-associated astrocytes (DAA) and oligodendrocyte precursor cells (OPC) are enriched in the outer shells surrounding the plaque-DAM complex. Hyperphosphorylated tau emerged mainly in excitatory neurons in the CA1 region accompanied by the infiltration of oligodendrocyte subtypes into the axon bundles of hippocampal alveus. The integrative STARmap PLUS method bridges single-cell gene expression profiles with tissue histopathology at subcellular resolution, providing an unprecedented roadmap to pinpoint the molecular and cellular mechanisms of AD pathology and neurodegeneration.

Abstract Background The role of viral infection in Alzheimer Disease (AD) pathogenesis is an area of great interest in recent years. Several studies have suggested an association between the human roseoloviruses, HHV-6 and HHV-7, and AD. Amyloid-β (Aβ) plaques are a hallmark neuropathological finding of AD and were recently proposed to have an antimicrobial function in response to infection. Identifying a causative and mechanistic role of human roseoloviruses in AD has been confounded by limitations in performing in vivo studies. Recent -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Murine roseolovirus (MRV) is a natural murine pathogen that is highly-related to the human roseoloviruses, providing an opportunity to perform well-controlled studies of the impact of roseolovirus on Aβ deposition. Methods We utilized the 5XFAD mouse model to test whether MRV induces Aβ deposition in vivo. We also evaluated viral load and neuropathogenesis of MRV infection. To evaluate Aβ interaction with MRV, we performed electron microscopy. RNA-sequencing of a cohort of AD brains compared to control was used to investigate the association between human roseolovirus and AD. Results We found that 5XFAD mice were susceptible to MRV infection and developed neuroinflammation. Moreover, we demonstrated that Aβ interacts with viral particles in vitro and, subsequent to this interaction, can disrupt infection. Despite this, neither peripheral nor brain infection with MRV increased or accelerated Aβ plaque formation. Moreover, −omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Our RNA-sequencing analysis of a cohort of AD brains compared to controls did not show an association between roseolovirus infection and AD. Conclusion Although MRV does infect the brain and cause transient neuroinflammation, our data do not support a role for murine or human roseoloviruses in the development of Aβ plaque formation and AD.

The most common type of dementia, Alzheimer’s disease, is associated with senile plaques formed by the filamentous aggregation of hydrophobic amyloid-β (Aβ) in the brains of patients. Small oligomeric assemblies also occur and drugs and chemical compounds that can interact with such assemblies have attracted much attention. However, these compounds need to be solubilized in appropriate solvents, such as ethanol, which may also destabilize their protein structures. As the impact of ethanol on oligomeric Aβ assembly is unknown, we investigated the effect of various concentrations of ethanol (0 to 7.2 M) on Aβ pentameric assemblies (Aβp) by combining blue native-PAGE (BN-PAGE) and ambient air atomic force microscopy (AFM). This approach was proven to be very convenient and reliable for the quantitative analysis of Aβ assembly. The Gaussian analysis of the height histogram obtained from the AFM images was correlated with band intensity on BN-PAGE for the quantitative estimation of Aβp. Our observations indicated up to 1.4 M (8.3%) of added ethanol can be used as a solvent/vehicle without quantitatively affecting Aβ pentamer stability. Higher concentration induced significant destabilization of Aβp and eventually resulted in the complete disassembly of Aβp.

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss of memory and other cognitive functions and the filamentous assembly of Aβ and tau in the brain. The assembly of Aβ peptides into filaments that end at residue 42 is a central event. Yang et al . used electron cryo–electron microscopy to determine the structures of Aβ42 filaments from human brain (see the Perspective by Willem and Fändrich). They identified two types of related S-shaped filaments, each consisting of two identical protofilaments. These structures will inform the development of better in vitro and animal models, inhibitors of Aβ42 assembly, and imaging agents with increased specificity and sensitivity. —SMH

All disease-targeting drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer′s disease patients. Even the recently approved drug Aducanumab, has proven effective in removing amyloid-β, but does not reduce cognitive decline. This emphasizes the urgent need for novel therapeutic approaches that could reduce several AD neuropathologies simultaneously, eventually leading to improved cognitive performance. To validate whether our mouse model replicates AD neuropathology as observed in patients, we characterized the 3xTg AD mouse model to avoid premature translation of successful results. In this study we have repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting the Wnt signaling and endosomal-lysosomal pathway respectively, to test their potential to attenuate AD pathology. Using intracerebral microdialysis, we simultaneously infused these disease-targeting drugs between 1-2 weeks, separately and also in combination, while collecting cerebrospinal fluid. We found that Fasudil reduces intracellular amyloid-β in young, and amyloid plaques in old animals, and overall cerebrospinal fluid amyloid-β. Lonafarnib reduces tau neuropathology and cerebrospinal fluid tau biomarkers in young and old animals. Co-infusion of both drugs was more effective in reducing intracellular amyloid-β than either drug alone, and appeared to improve contextual memory performance. However, an unexpected finding was that Lonafarnib treatment increased amyloid plaque size, suggesting that activating the endosomal-lysosomal system may inadvertently increase amyloid-β pathology if administered too late in the AD continuum. Taken together, these findings lend support to the application of repurposed drugs to attenuate AD neuropathology at various therapeutic time windows.

Structures of amyloid-β fibrils suggest Alzheimer’s disease–modifying strategies

Background: Cortical neuron loss is a pathological hallmark of late-onset Alzheimer's disease (AD). However, it remains unclear which neuronal subtypes are most vulnerable to degeneration and contribute most to cognitive decline. Methods: We analyzed postmortem bulk brain RNA-sequencing (RNAseq) data collected from three studies of aging and AD comprising six neocortical regions (704 individuals; 1037 samples). We estimated relative cell type proportions from each brain sample using neuronal subclass-specific marker genes derived from ultra-high depth single-nucleus RNAseq data (snRNAseq). We associated cell type proportions with AD across all samples using mixed-effects mega-analyses. Bulk tissue analyses were complemented by analyses of three AD snRNAseq datasets using the same cell type definitions and diagnostic criteria (51 individuals). Lastly, we identified cell subtype associations with specific neuropathologies, cognitive decline, and residual cognition. Results: In our mega-analyses, we identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β=-0.48, pbonf=8.98x10-9) and intra-telencephalic (IT) excitatory neurons (β=-0.45, pbonf =4.32x10-7). snRNAseq-based cell type proportion analyses especially supported the association of SST neurons. Analyses of cell type proportions with specific AD-related phenotypes in ROS/MAP consistently implicated fewer SST neurons with greater brain-wide postmortem tau and beta amyloid (β=-0.155, pFDR=3.1x10-4) deposition, as well as more severe cognitive decline prior to death (β=0.309, pFDR=3.9x10-6). Greater IT neuron proportions were associated strongly with improved cognition (β=0.173, pFDR=8.3x10-5) and residual cognition (β=0.175, pFDR=1.2x10-5), but not canonical AD neuropathology. Conclusions: Proportionally fewer SST and IT neurons were significantly associated with AD diagnosis across multiple studies and cortical regions. These findings support seminal work implicating somatostatin and pyramidal neurons in the pathogenesis of AD and improves our current understanding of neuronal vulnerability in AD.

Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

In Alzheimer's disease (AD), amyloid β deposition-induced hippocampal synaptic dysfunction generally begins prior to neuronal degeneration and memory impairment. Lycium barbarum extracts (LBE) have been demonstrated to be neuroprotective in various animal models of neurodegeneration. In this study, we aimed to investigate the effects of LBE on the synapse loss in AD through the avenue of the retina in a triple transgenic mouse model of AD (3xTg-AD). We fed 3xTg-AD mice with low (200 mg/kg) or high (2 g/kg) dose hydrophilic LBE daily for 2 months from the starting age of 4- or 6-month-old. For those started at 6 month age, at 1 month (though not 2 months) after starting treatment, mice given high dose LBE showed a significant increase of a wave and b wave in scotopic ERG. After 2 months of treatment with high dose LBE, calpain-2, calpain-5, and the oxidative RNA marker 8-OHG were downregulated, and presynaptic densities in the inner plexiform layer but not the outer plexiform layer of the retina were significantly increased, suggesting the presynaptic structure of retina was preserved. Our results indicate that LBE feeding may preserve synapse stability in the retina of 3xTg-AD mice, probably by decreasing both oxidative stress and intracellular calcium influx. Thus, LBE might have potential as a neuroprotectant for AD through synapse preservation.