Regina T. Vontell

Beta amyloid diffuse plaques, neurofibrillary tangles and neuritic plaques, are increased in densities at the intermediate stage of Alzheimer's neuropathological change. These pathological changes releasing Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs). These molecules are sensed by pattern recognition receptors (PRRs) and trigger intracellular responses. One response is the activation of the inflammasome sensors NLRP1, NLRP3, and AIM2 to oligomerize with ASC speck to form the inflammasome complex and initiate the downstream signaling of GSDMD mediated pyroptosis. Another response is the increase in genes to manufacture proinflammatory cytokines, the inflammasome formation activates the cleavage of the proinflammatory cytokines to the activated forms, which are secreted into the extracellular environment and recruit a widespread inflammation.

Neuritic plaques (NP) are a key component of Alzheimer disease (AD) pathology composed of dystrophic neurites that form neurofibrillary tangles (NFTs) and amyloid‐ β (A β ) proteins. NP accumulation is one fundamental feature seen in the intermediate stage of AD neuropathological pathology change. NPs are sites for cellular degeneration and can induce the upregulation of inflammatory signals including the inflammasome complex. We analyzed 758 genes using multiplex genomics in samples from the hippocampal, temporal and frontal brain regions that had intermediate AD neuropathological changes and aged‐matched controls. In addition, we analyzed NP formation using phosphorylated tau at threonine 217 (pTau217) and A β antibodies along with inflammasome sensors using NOD‐like receptor protein (NLRP) antibodies, apoptosis‐associated speck like protein containing a caspase recruitment domain (ASC) and absent in melanoma‐like receptor 2 (AIM2). Finally, we investigated if cell death is occurring cells by pyroptosis using Gasdermin D (GSDMD) antibody to detect pore formation on the membrane. Analyses show that inflammasome signaling genes and proteins are significantly increased in the hippocampus rather than the temporal and frontal lobe at the intermediate stage of AD. NPs are more prevalent in the hippocampus and temporal lobe in cases with intermediate AD pathology. ASC (1C100) immunostaining is colocalized with NLRP1, NLRP3 and AIM2. GSDMD immunostaining detected pericellular pores forming around the membrane of NFTs and in NPs. Messenger RNA and protein analyses demonstrate that inflammasome signaling molecules are elevated in AD suggesting that neuronal death occurs by the induction of pyroptosis.

CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental and psychiatric conditions. This resource consists of 9663 donors with array-based genotyping and 9543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 CNS diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing, normalized and annotated to describe their functional impact, resulting in 171 121 209 unique variants and 1 078 774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington’s disease, as well as associations of the APOE gene with Alzheimer’s disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort.

The study of neuronal electrical activity and spatial organization is essential for uncovering the mechanisms that regulate neuronal electrophysiology and function. Mathematical models have been utilized to analyze the structural properties of neuronal networks, predict connectivity patterns, and examine how morphological changes impact neural network function. In this study, we aimed to explore the role of the actin cytoskeleton in neuronal signaling via primary cilia and to elucidate the role of the actin network in conjunction with neuronal electrical activity in shaping spatial neuronal formation and organization, as demonstrated by relevant mathematical models. Our proposed model is based on the polygamma function, a mathematical application of ramification, and a geometrical definition of the actin cytoskeleton via complex numbers, ring polynomials, homogeneous polynomials, characteristic polynomials, gradients, the Dirac delta function, the vector Laplacian, the Goldman equation, and the Lie bracket of vector fields. We were able to reflect the effects of neuronal electrical activity, as modeled by the Van der Pol equation in combination with the actin cytoskeleton, on neuronal morphology in a 2D model. In the next step, we converted the 2D model into a 3D model of neuronal electrical activity, known as a core-shell model, in which our generated membrane potential is compatible with the neuronal membrane potential (in millivolts, mV). The generated neurons can grow and develop like an organoid brain based on the developed mathematical equations. Furthermore, we mathematically introduced the signal transduction of primary cilia in neurons. Additionally, we proposed a geometrical model of the neuronal branching pattern, which we described as ramification, that could serve as an alternative mathematical explanation for the branching pattern emanating from the neuronal soma. In conclusion, we highlighted the relationship between the actin cytoskeleton and the signaling processes of primary cilia. We also developed a 3D model that integrates the geometric organization unique to neurons, which contains soma and branches, such that the mathematical model represents the interaction between the actin cytoskeleton and neuronal electrical activity in generating action potentials. Next, we could generalize the model into a cluster of neurons, similar to an organoid brain model. This mathematical framework offers promising applications in artificial intelligence and advancements in neural networks.

Background: Neurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer’s disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology.Method: We investigated the protein expression, morphological differences of Ng and correlated Ng to hyperphosphorylated tau in the postmortem brains of 17 AD cases and 17 age and sex‐matched controls. In addition, we correlated the Ng expression with two different epitopes of apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC).Result: We show a reduction of Ng immunopositive neurons and morphological differences in AD compared to controls. Ng immunostaining was negatively correlated with neurofibrillary tangles, humanized anti‐ASC (IC100) positive neurons and anti‐ ASC positive microglia, in AD.Conclusion: The finding of a negative correlation between Ng and ASC speck protein expression in postmortem brains of AD suggests that the activation of inflammasome/ASC speck pathway may play an important role in synaptic degeneration in AD.

Central nervous system diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors including genetic risk. Here we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered in 15 broad categories by ICD-10 coding. These donors were collected by six repositories comprising the NIH NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants detected by Whole-Genome Sequencing (WGS) were called genome-wide and annotated to describe their functional impact, resulting in 171,121,209 unique mutations and 1,078,774 non-silent mutations. This whole-genome resource has been made available in the NIMH Data Archive ( nda.nih.gov ) and accompanying deep demographic and phenotypic descriptions are available at the NeuroBioBank Portal ( neurobiobank.nih.gov ). To illustrate an application of this resource, we replicated the strong association observed in previous studies between pathogenic CAG repeat expansions in the HTT gene with the clinical diagnosis of Huntington’s disease.

Dementia is a group of symptoms including memory loss, language difficulties, and other types of cognitive and functional impairments that affects 57 million people worldwide, with the incidence expected to double by 2040. Therefore, there is an unmet need to develop reliable biomarkers to diagnose early brain impairments so that emerging interventions can be applied before brain degeneration. Here, we performed biomarker analyses for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-β 42/40 (Aβ_42/40) ratio in the plasma of older adults. Participants had blood drawn at baseline and underwent two annual clinical and cognitive evaluations. The groups tested either cognitively normal on both evaluations (N_N), cognitively normal year 1 but cognitively impaired year 2 (N_I), or cognitively impaired on both evaluations (I_I). ASC was elevated in the plasma of the N_I group compared to the N_N and I_I groups. Additionally, Aβ₄₂ was increased in the plasma in the N_I and I_I groups compared to the N_N group. Importantly, the area under the curve (AUC) for ASC in participants older than 70 years old in N_N vs. N_I groups was 0.81, indicating that ASC is a promising plasma biomarker for early detection of cognitive decline.

Schizophrenia (SCZ) is a complex psychiatric disorder that involves an inflammatory response thought to be characterized by microglial activation. The inflammasome complex may play critical roles in the pathomechanism of neuroinflammation but how this relates to SCZ remains unclear. In this study, we performed an immunohistochemical (IHC) analysis to compare the expression of inflammasome proteins in brain tissue from donors with SCZ (n = 16) and non-psychiatric donors (NP; n = 13) isolated from the superior frontal cortex (SFC), superior temporal cortex, and anterior cingulate cortex brain regions. To assess changes in the cell populations that express key inflammasome proteins, we performed IHC analyses of apoptosis-associated speck-like protein containing a CARD (ASC), nod-like receptor protein 3 (NLRP3), and interleukin (IL)-18 to determine if these proteins are expressed in microglia, astrocytes, oligodendrocytes, or neurons. Inflammasome proteins were expressed mainly in microglia from SCZ and NP brains. Increased numbers of microglia were present in the SFC of SCZ brains and exhibited higher inflammasome protein expression of ASC, NLRP3, and IL-18 compared to NPs. These findings suggest that increased inflammasome signaling may contribute to the pathology underlying SCZ.

The development of the human central nervous system initiates in the early embryonic period until long after delivery. It has been shown that several neurological and neuropsychiatric diseases originate from prenatal incidents. Mathematical models offer a direct way to understand neurodevelopmental processes better. Mathematical modelling of neurodevelopment during the embryonic period is challenging in terms of how to ‘Approach’, how to initiate modelling and how to propose the appropriate equations that fit the underlying dynamics of neurodevelopment during the embryonic period while including the variety of elements that are built-in naturally during the process of neurodevelopment. It is imperative to answer where and how to start modelling; in other words, what is the appropriate ‘Approach’? Therefore, one objective of this study was to tackle the mathematical issue broadly from different aspects and approaches. The approaches were divided into three embryonic categories: cell division, neural tube growth and neural plate growth. We concluded that the neural plate growth approach provides a suitable platform for simulation of brain formation/neurodevelopment compared to cell division and neural tube growth. We devised a novel equation and designed algorithms that include geometrical and topological algorithms that could fit most of the necessary elements of the neurodevelopmental process during the embryonic period. Hence, the proposed equations and defined mathematical structure would be a platform to generate an artificial neural network that autonomously grows and develops.

INTRODUCTION: Neurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer's disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology. METHODS: We investigated the protein expression, morphological differences of Ng, and correlated Ng to hyperphosphorylated tau in the post mortem brains of 17 AD cases and 17 age‐ and sex‐matched controls. In addition, we correlated the Ng expression with two different epitopes of apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC). RESULTS: We show a reduction of Ng immunopositive neurons and morphological differences in AD compared to controls. Ng immunostaining was negatively correlated with neurofibrillary tangles, humanized anti‐ASC (IC100) positive neurons and anti‐ASC positive microglia, in AD. DISCUSSION: The finding of a negative correlation between Ng and ASC speck protein expression in post mortem brains of AD suggests that the activation of inflammasome/ASC speck pathway may play an important role in synaptic degeneration in AD. Highlights: We show the role that neurogranin plays on post‐synaptic signaling in specific hippocampal regions. We demonstrate that there could be clinical implications of using neurogranin as a biomarker for dementia. We describe the loss of plasticity and neuronal scaffolding proteins in the present of AD pathology. We show the response of neuroinflammation when tau proteins phosphorylate in hippocampal neurons. We show that there is a potential therapeutic target for the inflammasome, and future studies may show that IC100, a humanized monoclonal antibody directed against ASC, may slow the progression of neurodegeneration.