Translational Medicine Friday

microplastics, Microglial activation and Environmental toxins --- bigger issueS than we normally think

4/11/2025

Val's Take/Conjecture

When we think about Neuro-Developmental and Psychiatric Disorders --- there is not 1 gene or 1 environmental factor or epigenetic factor that accounts for everything.
- This very much sounds like Stanford Biology and Neurology Professor Robert Sapolsky --- "It doesn't work that way."

Many Neuro-Developmental and Psychiatric Disorders are being conceptualized as beginning IN UTERO and then having "a life of their own."

Environmental Toxins

9 News (Feb. 2025)
New study of human brains shows there are enough microplastics to make a spoon

["Life style choices" are important -- BUT if we don't understand how dysregulations IN UTERO affect lifestyle choices across the lifespan and make people more vulnerable to various disorders and diseases as a result of these prenatal dysregulations ----- there is a high likelihood we're going to get a partial, misleading answer.]

NLRP3 inflammasome as a sensor of micro- and nanoplastics immunotoxicity
(2023)

Polystyrene nanoplastics penetrate across the blood-brain barrier and induce activation of microglia in the brain of mice (2022)

[Are microplastics inducing perpetual activation of microglia in the brain?]

The Graduate (1967)
One word -- Plastics

Tomorrow’s Cure: How a lifetime of exposures impact health – exposome explained (2024)

Fitzgerald Lab
Division of Innate Immunity

Biology and Function of Inflammasomes

Polystyrene microplastics induce anxiety via HRAS derived PERK-NF-κB pathway (2024)

Microplastics in the Air May Be Leading to Lung and Colon Cancers

A review of 3,000 studies also suggests these minute plastic air particles may be causing male and female infertility.

Exposure to nano-polystyrene during pregnancy leads to Alzheimer's disease-related pathological changes in adult offspring (2025)

lactoferrin ---Selected recent research

4/11/2025

Val's Take/Conjecture

NOTE: I am NOT a doctor --- I'm not recommending any treatments.
On the other hand, I am recommending we investigate Lactoferrin further.

This is complicated, of course.

There is a study from 1982 showing that people with schizophrenia have MORE LACTOFERRIN.

At the time, this was thought to reflect an abnormal inflammatory response in people with schizophrenia.

Elevated serum levels of lactoferrin and eosinophil cationic protein in schizophrenic patients (1982)

See also:

Global Bibliometric and Visualized Analysis of Research on Lactoferrin from 1978 to 2024 (2024)

Lactoferrin deficiency during lactation increases the risk of depressive-like behavior in adult mice (2023)

Lactoferrin alleviates Western diet-induced cognitive impairment through the microbiome-gut-brain axis (2023)

"Thus, Lf [Lactoferrin] intervention alleviated cognitive impairment by inhibiting microglial activation and neuroinflammation through the microbiome-gut-brain axis."

The Lactoferrin Phenomenon-A Miracle Molecule (2022)

Abstract

Numerous harmful factors that affect the human body from birth to old age cause many disturbances, e.g., in the structure of the genome, inducing cell apoptosis [programmed cell death] and their degeneration, which leads to the development of many diseases, including cancer.

Among the factors leading to pathological processes, microbes, viruses, gene dysregulation and immune system disorders have been described.

The function of a protective agent may be played by lactoferrin as a "miracle molecule", an endogenous protein with a number of favorable antimicrobial, antiviral, antioxidant, immunostimulatory and binding DNA properties.

The purpose of this article is to present the broad spectrum of properties and the role that lactoferrin plays in protecting human cells at all stages of life.

Unlocking the power of Lactoferrin: Exploring its role in early life and its preventive potential for adult chronic diseases (2024)

Abstract

Nutrition during the early postnatal period exerts a profound impact on both infant development and later-life health.

Breast milk, which contains lactoferrin, a dynamic protein, plays a crucial role in the growth of various biological systems and in preventing numerous chronic diseases.

Based on the relationship between early infant development and chronic diseases later in life, this paper presents a review of the effects of lactoferrin in early life on neonates intestinal tract, immune system, nervous system, adipocyte development, and early intestinal microflora establishment, as well as the preventive and potential mechanisms of early postnatal lactoferrin against adult allergy, inflammatory bowel disease, depression, cancer, and obesity.

Furthermore, we summarized the application status of lactoferrin in the early postnatal period and suggested directions for future research.

Lactoferrin alleviates the adverse effects of early-life inflammation on depression in adults by regulating the activation of microglia (2025)

"Our findings suggest that lactoferrin intake during lactation protects neurons by regulating microglial activation, thereby effectively reducing depressive symptoms in adults."

Lactoferrin Attenuates Pro-Inflammatory Response and Promotes the Conversion into Neuronal Lineages in the Astrocytes (2025)

Maternal Immune activation, Fetal Inflammatory REsponse syndrome

4/8/2025

and MULTI-SYSTEM Neuro-developmental & Psychiatric Neuro-immune developmental disorders

Exposure to Maternal Immune Activation Causes Congenital Unfolded Protein Response Defects and Increases the Susceptibility to Postnatal Inflammatory Stimulation in Offspring (2021)

Conclusion:

Overall, MIA exposure in utero caused failure in UPR [unfolded protein response] as well as immune overreaction to the second attack of inflammation in offspring.

Our results suggested that prenatal exposure to MIA might contribute to the congenital inflammatory constitution after birth.

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders (2020)

Targeting Cytokine-Mediated Inflammation in Brain Disorders: Developing New Treatment Strategies (2025)

"Cytokine-mediated inflammation is increasingly recognized for playing a vital role in the pathophysiology of a wide range of brain disorders, including neurodegenerative, psychiatric, and neurodevelopmental problems. . . .

"As research advances, the creation of personalized, cytokine-centered therapeutics has the potential to alter the therapy landscape for brain illnesses, giving patients hope for better results and a higher quality of life."

Maternal immune activation and neuroinflammation in human neurodevelopmental disorders (2021)

Key points

Human studies are uncovering a role for maternal immune activation (MIA) in the pathogenesis of common neurodevelopmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome, in the offspring.

Prenatal, in utero and postnatal embedding of environmental factors in the epigenetic architecture of both the brain and the peripheral immune system can modulate individual susceptibility to neurodevelopmental disorders.

The effects of MIA, mediated by acute and chronic inflammation in pregnancy, are transduced to the fetus through inflammatory cell signalling pathways and epigenetic mechanisms.

Pathogen-associated molecular patterns, damage-associated molecular patterns and Toll-like receptors represent a convergent cellular pathway between heterogeneous environmental factors and innate immune activation.

In conjunction with individual genetic risk, sex-related factors and second ‘immune’ hits during life, MIA-induced aberrant immune programming results in a loss of immune homeostasis, which is associated with behavioural abnormalities in animal models.

Fetal inflammatory response and risk for psychiatric disorders (2023)

Children born to placentas meeting criteria for FIRS [Fetal Immune Response Syndrome] were more likely to be diagnosed with neuropsychiatric disorders.

Specifically, they were more likely to be diagnosed with

autism spectrum disorder,
conduct disorder,
adjusting for maternal history of
- psychiatric disorders,
- intra-partem substance use, and
- prescriptions of anti-inflammatory drugs.
Children born with placental inflammation are at an increased risk to develop neuropsychiatric disorders.
This has profound implications for future research, and early detection, monitoring, and treatment in these children.

Anti-psychotics and Glial cells

4/6/2025

Val's Take/Conjecture

With respect to Psychiatric Medications ---- some of them are affecting Microglia both positively and negatively.

The antipsychotic chlorpromazine reduces neuroinflammation by inhibiting microglial voltage-gated potassium channels (2025)
*Korean Researchers

"This review will provide a summary of the dual role of antipsychotics on neurochemical parameters associated with glial functions and will highlight the potential activity of glio-protective molecules to improve the action of antipsychotics."

Olanzapine, Risperidone and Clozapine prescribing is associated with increased risk for Alzheimer’s Disease reflecting antipsychotic-specific effects on microglial phagocytosis (2023)
*UK & Swedish Researchers

The Janus face of antipsychotics in glial cells: Focus on glio-protection (2023)
*Brazilian & German Researchers

Mitochondrial Dysfunction

3/31/2025

Val's Take: More and more Researchers are moving beyond DSM symptom clusters to INDIVIDUALIZED PRECISION MEDICINE and BIOLOGICAL MECHANISMS such as cell types, organelles, DNA, RNA, epigenetics, molecular pathways, the microbiome, the endocrine system, the immune system and yes the brain and the central nervous system and their relationships to each other trans-generationally, developmentally and over the life span.

My understanding is that it was Researchers and Clinicians addressing Orphan Mitochondrial Diseases that only effect a small number of people --- who started to point out that MOST DISEASE and DISORDER involve some type of Mitochondrial Dysfunction --- as it turns out they were right.

What I particularly appreciate about Dr. Madsen's video is that he appreciates the importance of Diet and Exercise while at the same time understanding that will often not be sufficient alone.

Additionally, Dr. Madsen as others are pointing out the significant role of modern Environmental Toxins --- which like Climate Change is hugely inconvenient.

Finally, the Reverse Aging Revolution folks understand that Mitochondrial Dysfunction ultimately affects everyone through the Aging Process ---- some of us sooner than others --- but Mitochondrial Dysfunction is of universal concern.

Unravelling the Brain with Dr. Josh Madsen
The Hidden Crisis of Autism & Mitochondrial Dysfunction Explained (2025)

Reverse Aging Revolution
Producing Young Mitochondria Accessible For Everyone - Mitochondrial Transplantation For Longevity (2024)

One thing leads to another

3/16/2025

Val's Take: "You told me something wrong --- I know I listen too long --- but one thing leads to another --- I know you been lying to me."

I don't think the Mental Health Profession has been "lying to me," but . . .

There are major problems that are not being addressed in this gap between the researchers and the clinicians.

Once we go from Neuro-Developmental and Psychiatric Disorders as Brain Disorders --- to Multi-System Neuro Immune Disorders --- that implicates other medical disciplines.

"The wrong antidote is like a bone in the throat."

The hard issues regarding the Shaky Foundation of Psychiatric Diagnostics

The DSM 5 and the Criminal Justice Wheel of Fortune

New Understandings Matter

Science Up

fetal microglia, inflammation & neuronal Hyper-excitoxicity in neuro-developmental & Psychiatric Disorders

3/8/2025

Val's Take/ Conjecture

It's more complicated than this --- but Microglia are essentially the Brain's Innate Immune Cells.
Maternal Immune Activation appears to effect adult behavior by among other things:
- Dysregulating Amoeboid Microglia during pregnancy. Those Amoeboid Microglia ultimately become
- Ramified Microglia in the Adult Central Nervous System

Astrocytes are another type of glial cell, different than Microglia.
Astrocytes do a number of things, including maintaining glutamate homeostasis.
Glutamate excitotoxicity is involved with Neuro-Developmental and Psychiatric Disorders.

Microglial contribution to the pathology of neurodevelopmental disorders in humans (2023)

Dysfunctional mitochondrial processes contribute to energy perturbations in the brain and neuropsychiatric symptoms (2023)

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders (2024)

"In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders.

"Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions."

"Our mission: to help accelerate the next breakthrough in drug discovery, diagnostics and basic research."

Microglia subtype markers
(2022)

Amoeboid microglia
- Amoeboid microglia are associated with the developing CNS. In rats, amoeboid microglia have been shown to appear late in gestation and disappear soon after birth.
- Ultimately, amoeboid microglia grow long crenulated processes and transform into ramified microglia found in the adult CNS.
Ramified microglia
Reactive microglia
- Like macrophages, reactive microglia secrete inflammatory mediators, which orchestrate the cerebral immune response.

Chronic microglial activation is associated with neurological disorders including Alzheimer's disease, multiple sclerosis, and delayed neuronal death occurring after ischaemia.

In these instances, the persistent activation of microglia accompanied by the sustained secretion of inflammatory mediators is thought to have a deleterious effect on neuronal function and survival, thereby exacerbating disease processes.

CD45 - microglia
CD45 - macrophage
CD11b
CD68 - microglia
CD68 - macrophage

Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release (2019)

Metabolism & Maternal Immune activation

3/2/2025

Val's Take/Conjecture

One of many things making these insights hard to come by beyond the need for advanced technology is that Neuro-Diversity is characterized by DIVERSITY.
Further, METABOLIC DYSREGULATION is different in different people --- it doesn't necessarily look the same.

Dysregulation of immune and metabolism pathways in maternal immune activation induces an increased risk of autism spectrum disorders (2023)

Key findings: A novel evidence was proved that illustrated altering four immune and metabolism-related risk pathways, including starch and sucrose metabolism, ribosome, protein processing in endoplasmic reticulum, and retrograde endocannabinoid signaling pathway, which were prominent involvement in the process of MIA regulating abnormal fetal brain development to induce an increased risk of ASD.

Here, we have observed that almost all key genes within these risk pathways are significantly differentially expressed at embryonic days (E) 10.5-12.5, which is considered to be the optimal coincidence window of mouse embryonic brain development to study the intimate association between MIA and ASD using mouse animal models.

Significance: [The] search establishes that MIA causes dysregulation of immune and metabolic pathways, which leads to abnormal embryonic neurodevelopment, thus promoting development of ASD symptoms in offspring.

Shared genetic architecture and bidirectional clinical risks within the psycho-metabolic nexus (2025)

Interpretation: The study highlights the intertwined genetic and clinical relationships between psychiatric disorders and metabolic dysregulations, emphasizing the need for integrated approaches in diagnosis and treatment.

Molecular and metabolic heterogeneity of astrocytes and microglia (2023)

Abstract

Astrocytes and microglia are central players in a myriad of processes in the healthy and diseased brain, ranging from metabolism to immunity.

The crosstalk between these two cell types [Astrocytes & Microglia] contributes to pathology in many if not all neuroinflammatory and neurodegenerative diseases.

Recent advancements in integrative multimodal sequencing techniques have begun to highlight how heterogeneous both cell types are and the importance of metabolism to their regulation.

We discuss here the transcriptomic, metabolic, and functional heterogeneity of astrocytes and microglia and highlight their interaction in health and disease.

Sensory processing, Synapses, Energy, the Immune System & Emotional Dysregulation

2/28/2025

Val's Take/Conjecture

Carly is not a person with an "INVISIBLE DISABILITY" --- people around her knew she had some challenges even if they misunderstood the nature of those challenges.
CARLY IS A SLOW PROCESSOR AND SHE IS INTELLIGENT.

Most people with ADHD, Autism, Dyslexia, etc. have invisible disabilities --- that is most other people do not see the disability-- and they also often do not see the need for accommodation.

And that also often includes the person themselves.
Even though I'm not a big fan of DSM 5 diagnostic categories --- they can alert people that there is an issue.
Like the situation for Carly, the true nature of the challenges is often misunderstood.

Microglia: Synaptic modulator in autism spectrum disorder (2022)

"Mounting evidence indicates that microglia, the resident immune cells of the brain, are required for proper brain function, especially in the maintenance of neuronal circuitry and control of behavior.

"Dysfunction of microglia will ultimately affect the neural function in a variety of ways, including the formation of synapses and alteration of excitatory-inhibitory balance."

Mitochondrial Biogenesis in Neurons: How and Where (2021)

"Neurons rely mostly on mitochondria for the production of ATP and Ca2+ (Calcium ion) homeostasis."

Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation (2025)

Burden of Proof

More Conjecture

Greater sensory processing demands as the result of greater number of synapses
- create greater ENERGY needs in people with Neuro-Developmental and Psychiatric Disorders .
The CATCH-22: Many of these Neuro-Developmental & Psychiatric Disorders have idiosyncratic and varied "DYSREGULATIONS," including Metabolic Dysregulations involving Mitochondria, and Microglia -- the Brain's Innate Immune Cells.
It it is very hard to say current understandings are TOTALLY WRONG --- but newer understandings go back in the CHAIN OF CAUSALITY and explain things that current understandings often do get wrong.
Further, researchers are not done yet.

Star Institute posted this 20/20 episode on YouTube in 2012.
Star Institute is in Centennial, Colorado.

The video is of Carly Fleishmann with non-verbal autism.

What about the kid or adult who is verbal but is nonetheless getting overwhelmed with sensory input of one or more types?

Concepts of Neuroinflammation and Their Relationship With Impaired Mitochondrial Functions in Bipolar Disorder (2021)

Abstract

Bipolar disorder (BD) is a chronic psychiatric disease, characterized by frequent behavioral episodes of depression and mania, and neurologically by dysregulated:

neurotransmission,
neuroplasticity [for people with ADHD and/or Autism they may have hyper-plasticity],
growth factor signaling, and
metabolism,
as well as oxidative stress, and
neuronal apoptosis [apoptosis is a type of cell death],
contributing to chronic neuroinflammation.

These abnormalities result from complex interactions between multiple susceptibility genes and environmental factors such as stress.

The neurocellular abnormalities of BD can result in gross morphological changes, such as reduced prefrontal and hippocampal volume, and circuit reorganization resulting in cognitive and emotional deficits.

The term "neuroprogression" is used to denote the progressive changes from early to late stages, as BD severity and loss of treatment response correlate with the number of past episodes.

In addition to circuit and cellular abnormalities, BD [Bipolar Disorder] is associated with dysfunctional mitochondria, leading to severe metabolic disruption in high energy-demanding neurons and glia.

[synapses are the connections between neurons not the neurons themselves but synapses take a lot of energy too]

Indeed, mitochondrial dysfunction involving electron transport chain (ETC) disruption is considered the primary cause of chronic oxidative stress in BD.

The ensuing damage to:

membrane lipids,
proteins, and
DNA
further perpetuates oxidative stress and neuroinflammation,
creating a perpetuating pathogenic cycle.

A deeper understanding of BD [Bipolar Disorder] pathophysiology and identification of associated biomarkers of neuroinflammation are needed to facilitate early diagnosis and treatment of this debilitating disorder.

The Immune Frontier in PsychiatryDecades in the making -- It is ready to take a starring role

2/24/2025

Val's Take/Conjecture

The journal Brain, Behavior and Immunity was started in 1987 by the Psychoneuroimmunology Research Society (PNIRS).
The journal publishes peer-reviewed basic, experimental, and clinical studies dealing with behavioral, neural, endocrine, and immune system interactions in humans and animals.
They were really on to something.

It's starting to become relatively CLEAR how something like MATERNAL IMMUNE ACTIVATION could be a big factor in Neuro-Developmental and Psychiatric Disorders.

"Inflammation" is a common term in the society and it's probably not going to be too long before "Maternal Immune Activation" is widely known even if people aren't familiar with all the complexity of that.

Low-dose interleukin-2 in patients with bipolar depression: A phase 2 randomised double-blind placebo-controlled trial (2025)

"This proof-of-concept trial shows that stimulating Tregs [Regulatory T cells] in patients with bipolar depression is safe and associated with clinical improvements.

"This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2LD as an adjunct treatment of major mood disorders."

Influence of Immune System Abnormalities Caused by Maternal Immune Activation in the Postnatal Period (2023)

"Exposure to maternal immune activation is a risk factor for neurodevelopmental disorders, psychosis, cardiovascular diseases, metabolic diseases, and human immune disorders.

"It has been associated with increased levels of proinflammatory cytokines transferred from mother to fetus in the prenatal period."

Understanding immune system dysfunction and its context in mood disorders: psychoneuroimmunoendocrinology and clinical interventions (2024)

Conventional and new immunotherapies for immune system dysregulation in postpartum mood disorders: comparisons to immune system dysregulations in bipolar disorder, major depression, and postpartum autoimmune thyroid disease (2025)

Cognitive disorders in patients with neuroimmunological disease (2025)

Summary: Autoimmune diseases should be considered as critical causal factors underlying new cases of neurocognitive disorder, especially in young patients.

These diseases are mediated by immune system reactions involving antibody production, T-cell-mediated damage, and demyelination.

Although the prognosis seems favourable in most conditions after immunotherapy, the magnitude of the therapeutic effect of immunotherapy on cognitive functioning remains unclear.

Chronological versus immunological aging: Immune rejuvenation to arrest cognitive decline (2025)

Abstract

The contemporary understanding that the immune response significantly supports higher brain functions has emphasized the notion that the brain's condition is linked in a complex manner to the state of the immune system.

It is therefore not surprising that immunity is a key factor in shaping brain aging. In this perspective article, we propose amending the Latin phrase "mens sana in corpore sano" ("a healthy mind in a healthy body") to "a healthy mind in a healthy immune system."

Briefly, we discuss the emerging understanding of the pivotal role of the immune system in supporting lifelong brain maintenance, how the aging of the immune system impacts the brain, and how the potential rejuvenation of the immune system could, in turn, help revitalize brain function, with the ultimate ambitious goal of developing an anti-aging immune therapy.

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