Andrew S. Mendiola

• Ph.D.
• PostDoc Position at Gladstone Institutes

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell at...

In this issue of Neuron, Shi et al. (2021) show a protective role for the low-density lipoprotein receptor (LDLR) in tau pathology. Brain overexpression of LDLR lowers apolipoprotein E (apoE), suppresses microglial activation, preserves myelin, and ameliorates neurodegeneration, pointing the way toward potential new therapies.

Blood protein extravasation through a disrupted blood–brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipe...

Computer-vision and machine-learning (ML) approaches are being developed to provide scalable, unbiased, and sensitive methods to assess mouse behavior. Here, we used the ML-based variational animal motion embedding (VAME) segmentation platform to assess spontaneous behavior in humanized App knockin and transgenic APP models of Alzheimer’s disease (...

Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1–4. Despite the clinical evidence1,5–7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain po...

Diabetic retinopathy, a microvascular disease characterized by irreparable vascular damage, neurodegeneration and neuroinflammation, is a leading complication of diabetes mellitus. There is no cure for DR, and medical interventions marginally slow the progression of disease. Microglia-mediated inflammation in the diabetic retina is regulated via CX...

Summary statement: Diabetic human and murine retinas revealed pronounced microglial morphological activation and vascular abnormalities associated with inflammation. Pharmacological fibrinogen depletion using ancrod dampened microglial morphology alterations, resolved fibrinogen accumulation, rescued axonal integrity, and reduced inflammation in t...

Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 limits the activation of pathogenic microglia and the human polymorphic CX3CR1I249/M280 (hCX3CR1I249/M280) variant increases disease progression in models of MS. However, the role of hCX3CR1I249/M280 variant on microglial activation and central n...

Microglia-mediated inflammation plays a significant role in neuronal and vascular damage in diabetic retinopathy, but the mechanism linking inflammation, neurodegeneration, and impaired vascular integrity is still unclear. Our previous studies from diabetic mouse models showed accumulation of fibrinogen, at vessel lesions surrounded by perivascular...

Extrinsic inhibitors at sites of blood–brain barrier disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome the extrinsic inhibition of remyelination are not widely available and the dynamics of glial progenitor niche remodeling at sites of neurovascular dysfunction are large...

Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 regulates the activation of pathogenic microglia in models of MS and the human polymorphic CX3CR1 I249/M280 (hCX3CR1 I249/M280 ) variant increases MS disease progression. However, the role of hCX3CR1 I249/M280 on microglial activation and central...

Central nervous system (CNS) lymphoma is an extranodal non-Hodgkin B-cell lymphoma characterized by malignant lymph tissue arising in the brain or spinal cord, associated with inflammation and blood-brain barrier (BBB) disruption. Although BBB disruption is known to occur in patients with CNS lymphoma, a direct link between these two has not been s...

Microglial surveillance is a key feature of brain physiology and disease. Here, we found that Gi-dependent microglial dynamics prevent neuronal network hyperexcitability. By generating MgPTX mice to genetically inhibit Gi in microglia, we show that sustained reduction of microglia brain surveillance and directed process motility induced spontaneous...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Extracellular vesicles (EVs) are emerging as potent mediators of intercellular communication with roles in inflammation and disease. In this study, we examined the role of EVs from blood plasma (pEVs) in an experimental autoimmune encephalomyelitis mouse model of central nervous system demyelination. We determined that pEVs induced a spontaneous re...

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer’s disease (AD). However, the mechanisms that link disruption of the blood–brain barrier (BBB) to neurodegeneration are poorly understood, and exp...

Signature profile of brain and blood leukocytes. Activation of brain and spinal cord microglia (CD45LoCD11b+) and infiltrating macrophages (CD45HiCD11b+Ly6C+) was assessed by flow cytometric assessment of median fluorescence intensity as a representation of abundancy of MHC-II (left panels), CD11b (middle panels) and CD86 (right panels) molecules....

Quantitative validation of energetics and stereochemistry. (A) The proposed structural models were built using the prediction software Phyre2, Swiss-assessment structure suite that provides energetic values and the RAMPAGE software that characterizes the stereochemistry of the proposed model from measurement of dihedral angles with Ramachandran gra...

Genes significantly regulated in CX3CR1-WT microglia in comparison to naïve microglia.

Genes significantly regulated in CX3CR1-KO microglia in comparison to naïve microglia.

IL-17 and IFN-γ production by CD4+ and CD8+ T cells in EAE affected mice. (A) Brain and spinal cord mononuclear cells isolated over percoll gradients were subjected to imaging flow cytometry with gating strategy based on singlet population, followed by CD4 and CD8 T cell separation and IFN-γ and IL-17 discrimination. (B) Images show that double pos...

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS) is the leading cause of non-traumatic neurological disability in young adults. Immune mediated destruction of myelin and oligodendrocytes is considered the primary pathology of MS, but progressive axonal loss is the major cause of neurological disabil...

It is becoming increasingly clear that neuroinflammation has a causal role in the pathogenesis of central nervous system (CNS)-related diseases, and therefore therapeutic strategies targeting the regulation or availability of inflammatory mediators can be used to prevent or mitigate pathology. Interestingly, the proinflammatory cytokine, interleuki...

Multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS is the leading cause of nontraumatic neurological disability in young adults. Immune mediated destruction of the myelin and oligodendrocytes are considered its primary pathology, but progressive axonal loss is the major cause of neurological disability. In an effort to unders...

Inflammatory demyelination is a hallmark of the pathology of multiple sclerosis (MS) and microglia are considered responsible for exacerbating myelin loss. The link between inflammation and neural stem cell (NSC) development, key events during the remyelination process, is being increasingly recognized. However, the mechanisms that connect microgli...

Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in...

Fractalkine (FKN) is a chemokine expressed constitutively by healthy neurons and signals to microglia upon interaction with the FKN receptor, CX3CR1. Signaling between FKN and CX3CR1 transduces inhibitory signals that ameliorate microglial activation and proinflammatory cytokine release in neuroinflammatory conditions. The aim of this study is to d...

PurposeOne of the earliest hallmarks of diabetic retinopathy is the loss of retinal pericytes. However, the mechanisms that promote pericyte dropout are unknown. In the present study, we propose a novel pathway in which pericyte apoptosis is mediated by macrophages, TGFβ and pro-apoptotic BIGH3 (TGFβ-induced Gene Human Clone 3) protein.Patients and...

Conventional dendritic cells (DCs) are critical for protection against pulmonary infection with the opportunistic fungal pathogen Cryptococcus neoformans; however, the role of plasmacytoid DCs (pDCs) is unknown. We show for the first time that pDCs have direct activity against C. neoformans via reactive oxygen species (ROS); a mechanism different f...

It’s known that diabetics are more susceptible to infections and there is an association between diabetes and chronic inflammation, but whether systemic inflammation contributes to retinopathy remains unknown. Microglial-mediated inflammation has gained recognition as a key contributor to diabetic retinopathy (DR) pathogenesis. We have shown that s...

Fractalkine (CX3CL1 or FKN) is a membrane-bound chemokine expressed on neuronal membranes and is proteolytically cleaved to shed a soluble chemoattractant domain. FKN signals via its unique receptor CX3CR1 expressed on microglia and other peripheral leukocytes. The aim of this study is to determine the role of CX3CR1 in inflammatory-mediated damage...

There is growing evidence that chronic inflammation plays a role in both the development and progression of diabetic retinopathy. There is also evidence that molecules produced as a result of hyperglycemia can activate microglia. However the exact contribution of microglia, the resident immune cells of the central nervous system, to retinal tissue...