Bradlee Heckmann

Last updated
Bradlee L. Heckmann
Heckmann ADPD.png
Born
Lexington, Kentucky, U.S.
Other namesBrad Heckmann
Alma mater Mayo Clinic College of Medicine and Science

University of Kentucky
Known forDiscovery of LC3-associated endocytosis
Scientific career
Fields Neuroimmunology
autophagy
Alzheimer's disease
Parkinson's disease
Institutions University of South Florida

Asha Therapeutics

St. Jude Children's Research Hospital
Thesis The function and regulation of the G0/G1 Switch Gene 2
Doctoral advisor Jun Liu
Other academic advisors Douglas R. Green
Edmund B. Rucker, III
Website www.ashatherapeutics.com
www.health.usf.edu
www.heckmannlab.org

Bradlee L. Heckmann is an American biologist, pharmacologist. Heckmann holds academic appointments as a neuroimmunologist at the Byrd Alzheimer's Center and USF Health Neuroscience Institute and is assistant professor in molecular medicine at the USF Health Morsani College of Medicine. Heckmann's research has been focused on understanding the regulation of inflammatory and metabolic processes in the central nervous system, with particular emphasis on neurodegenerative diseases including Alzheimer's disease [1] and the role of the autophagy machinery in this setting.

Contents

Education

Heckmann graduated from Lexington Catholic High School in Lexington, Kentucky prior to attending the University of Kentucky, where he graduated with a Bachelor of Science in biology. Heckmann went on to complete his doctoral training in Biochemistry & Molecular Biology at the Mayo Clinic College of Medicine. [2] After completing his formal training he joined the laboratory of Douglas R. Green at St. Jude Children's Research Hospital where he held the John H. Sununu Endowed Fellowship [3] in immunology. [4]

Research

After studying lipid metabolism and components that regulate lipid turnover while at Mayo Clinic, Heckmann switched his research focus to evaluating the role and regulation of non-canonical autophagy in the brain. [5] [6] These studies ultimately led to Heckmann & Green's discovery of a novel form of the endocytic trafficking pathway. [7] Heckmann and Green showed that a protein known as LC3 which helps facilitate vesicle trafficking and fusion, most well known for its role in autophagy, was attached to endosomes that contained β-amyloid, [7] a known contributor to Alzheimer's Disease establishment and pathology in humans. As such they named the discovery LC3-associated endocytosis (LANDO). [8] [9] [10] They further found that inhibition of LC3-associated endocytosis in microglial immune cells of the brain resulted in impaired recycling of cell receptors that recognize β-amyloid, leading to dramatic increases in inflammatory activation. [7]

Heckmann and Green were the first to show that loss of the LC3-associated endocytosis pathway in microglia greatly exacerbated the disease pathology of Alzheimer's Disease and that the LANDO pathway is protective against β-amyloid induced neuroinflammation and neurodegeneration, work recently published in Cell [7] and featured in mainstream media. [11] [12] [13] [9] [10] [8]

The potential for therapeutically targeting LC3-associated endocytosis for the treatment of devastating conditions including Alzheimer's Disease and cancer is of significant promise. [8] Additional evidence supporting a significant role for LANDO and other non-canonical uses of the autophagy machinery in neurodegeneration and neuroinflammation were recently published by Drs. Heckmann and Green along with other colleagues including Thomas Wileman demonstrating an important role for LANDO and targeting of neuroinflammation as a therapeutic approach to relieving neuronal and behavioral impairment in a novel, age-associated spontaneous model of Alzheimer's Disease in mice, work that has been published in Science Advances. [14]

More recently, the Heckmann Lab has been exploring new roles for the LANDO pathway in regulating cell death processes in neurodegeneration as well as contribution of metabolic mechanisms and mitochondrial regulation to neuroinflammation. [15] Heckmann has also expanded his interests in neuro-oncology and primary brain tumor biology and the role of single membrane LC3-lipidation (CASM) pathways to tumor immunity and tumor microenvironment inflammation.

Recognition and awards

Heckmann has received multiple awards and honors stemming from his work primarily on LC3-associated endocytosis as well as mainstream media coverage. [16] [17] [18] He has been the recipient of honors including a Ruth L. Kirschstein National Research Service Award, an Aegean Young Investigator Award, an LRP award from the National Cancer Institute, and an Excellence in Science Award and nomination for Prize in Neurobiology from the American Association for the Advancement of Science. [19] [20] Dr. Heckmann was recently[ when? ] featured by AZO Network and News Medical as a "thought leader in medicine". [21]

Work from Heckmann and his laboratory on LANDO and autophagy in Alzheimer's Disease was recently highlighted by Research Features and an associated podcast including potential new therapeutic routes for treating neurodegenerative diseases. [22]

He also has been elected as a member of the Sigma Xi Research Honor Society and is an overseas Fellow of the Royal Society of Medicine.

Related Research Articles

<span class="mw-page-title-main">Cerebral amyloid angiopathy</span> Disease of blood vessels of the brain

Cerebral amyloid angiopathy (CAA) is a form of angiopathy in which amyloid beta peptide deposits in the walls of small to medium blood vessels of the central nervous system and meninges. The term congophilic is sometimes used because the presence of the abnormal aggregations of amyloid can be demonstrated by microscopic examination of brain tissue after staining with Congo red. The amyloid material is only found in the brain and as such the disease is not related to other forms of amyloidosis.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">AP2 adaptor complex</span>

The AP2 adaptor complex is a multimeric protein that works on the cell membrane to internalize cargo in clathrin-mediated endocytosis. It is a stable complex of four adaptins which give rise to a structure that has a core domain and two appendage domains attached to the core domain by polypeptide linkers. These appendage domains are sometimes called 'ears'. The core domain binds to the membrane and to cargo destined for internalisation. The alpha and beta appendage domains bind to accessory proteins and to clathrin. Their interactions allow the temporal and spatial regulation of the assembly of clathrin-coated vesicles and their endocytosis.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

Autophagin-1 (Atg4/Apg4) is a unique cysteine protease responsible for the cleavage of the carboxyl terminus of Atg8/Apg8/Aut7, a reaction essential for its lipidation during autophagy. Human Atg4 homologues cleave the carboxyl termini of the three human Atg8 homologues, microtubule-associated protein light chain 3 (LC3), GABARAP, and GATE-16.

<span class="mw-page-title-main">LRP1</span> Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

<span class="mw-page-title-main">Hydroxycarboxylic acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors, HCA1 and HCA3, HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA2.

<span class="mw-page-title-main">TREM2</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 2(TREM2) is a protein that in humans is encoded by the TREM2 gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

Hirano bodies are intracellular aggregates of actin and actin-associated proteins first observed in neurons by Asao Hirano in 1965. The eponym ‘Hirano bodies’ was not introduced until 1968, by Schochet et al., three years after Hirano first observed the proteins.

Samuel E. Gandy, is a neurologist, cell biologist, Alzheimer's disease (AD) researcher and expert in the metabolism of the sticky substance called amyloid that clogs the brain in patients with Alzheimer's. His team discovered the first drugs that could lower the formation of amyloid.

<span class="mw-page-title-main">Rudolph E. Tanzi</span> American geneticist

Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, vice-chair of neurology, director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH).

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

<span class="mw-page-title-main">Urtė Neniškytė</span> Lithuanian neuroscientist (b. 1983)

Urtė Neniškytė is a Lithuanian neuroscientist. Her scientific interest and main area of work relates to the interaction of neurons and immune cells in the brain. She has studied the cellular mechanisms of Alzheimer's disease and is the co-author of the first articles about cell death in relation to phagocytosis.

<span class="mw-page-title-main">Phenserine</span> Chemical compound

Phenserine is a synthetic drug which has been investigated as a medication to treat Alzheimer's disease (AD), as the drug exhibits neuroprotective and neurotrophic effects.

<span class="mw-page-title-main">Katerina Akassoglou</span> Greek neuroimmunologist

Katerina Akassoglou is a neuroimmunologist who is a Senior Investigator and Director of In Vivo Imaging Research at the Gladstone Institutes. Akassoglou holds faculty positions as a Professor of Neurology at the University of California, San Francisco. Akassoglou has pioneered investigations of blood-brain barrier integrity and development of neurological diseases. She found that compromised blood-brain barrier integrity leads to fibrinogen leakage into the brain inducing neurodegeneration. Akassoglou is internationally recognized for her scientific discoveries.

<span class="mw-page-title-main">Experimental models of Alzheimer's disease</span>

Experimental models of Alzheimer's disease are organism or cellular models used in research to investigate biological questions about Alzheimer's disease as well as develop and test novel therapeutic treatments. Alzheimer's disease is a progressive neurodegenerative disorder associated with aging, which occurs both sporadically or due to familial passed mutations in genes associated with Alzheimer's pathology. Common symptoms associated with Alzheimer's disease include: memory loss, confusion, and mood changes.

<span class="mw-page-title-main">Rubicon (protein)</span> Human protein involved in autophagy regulation

Rubicon is a protein that in humans is encoded by the RUBCN gene. Rubicon is one of the few known negative regulators of autophagy, a cellular process that degrades unnecessary or damaged cellular components. Rubicon is recruited to its sites of action through interaction with the small GTPase Rab7, and impairs the autophagosome-lysosome fusion step of autophagy through inhibition of PI3KC3-C2.

Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), Apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and Clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.

Alzheimer's disease (AD) is a complex neurodegenerative disease that affects millions of people across the globe. It is also a topic of interest in the East Asian population, especially as the burden of disease increases due to aging and population growth. The pathogenesis of AD between ethnic groups is different. However, prior studies in AD pathology have focused primarily on populations of European ancestry and may not give adequate insight on the genetic, clinical, and biological differences found in East Asians with AD. Gaps in knowledge regarding Alzheimer's disease in the East Asian population introduce serious barriers to screening, early prevention, diagnosis, treatment, and timely intervention.

References

  1. ↑ Heckmann, Bradlee L.; Tummers, Bart; Green, Douglas R. (January 2019). "Crashing the computer: apoptosis vs. necroptosis in neuroinflammation". Cell Death & Differentiation. 26 (1): 41–52. doi: 10.1038/s41418-018-0195-3 . PMC   6294765 . PMID   30341422.[ non-primary source needed ]
  2. ↑ Heckmann, Bradlee Lawrence (2016). The function and regulation of the G0/G1 Switch Gene 2 (G0S2) (Thesis).[ page needed ][ non-primary source needed ]
  3. ↑ ORCID. "Bradlee L. Heckmann (0000-0002-3271-7183)". orcid.org. Retrieved 2020-04-01.
  4. ↑ "Postdoctoral Fellows". www.stjude.org. Retrieved 2020-04-01.
  5. ↑ Heckmann, Bradlee L.; Green, Douglas R. (1 March 2019). "LC3-associated phagocytosis at a glance". Journal of Cell Science. 132 (5). doi: 10.1242/jcs.222984 . PMC   6432721 . PMID   30787029.[ non-primary source needed ]
  6. ↑ Heckmann, Bradlee L.; Boada-Romero, Emilio; Cunha, Larissa D.; Magne, Joelle; Green, Douglas R. (November 2017). "LC3-Associated Phagocytosis and Inflammation". Journal of Molecular Biology. 429 (23): 3561–3576. doi:10.1016/j.jmb.2017.08.012. PMC   5743439 . PMID   28847720.[ non-primary source needed ]
  7. 1 2 3 4 Heckmann, Bradlee L.; Teubner, Brett J.W.; Tummers, Bart; Boada-Romero, Emilio; Harris, Lacie; Yang, Mao; Guy, Clifford S.; Zakharenko, Stanislav S.; Green, Douglas R. (July 2019). "LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease". Cell. 178 (3): 536–551.e14. doi: 10.1016/j.cell.2019.05.056 . PMC   6689199 . PMID   31257024. (Erratum:  doi:10.1016/j.cell.2020.11.033, PMID   33306957 . If the erratum has been checked and does not affect the cited material, please replace {{ erratum |...}} with {{ erratum |...|checked=yes}}.)[ non-primary source needed ]
  8. 1 2 3 Jefferson, Robin Seaton. "Newly Discovered Cellular Pathway May Mean New Approach For How We Treat Alzheimer's And Cancer". Forbes. Retrieved 2020-04-01.
  9. 1 2 Hospital, About The Author Mary Powers Mary Powers is a member of the Communications Department at St Jude Children’s Research (2019-07-25). "Lando: Star Wars smuggler or possible ally against Alzheimer's disease?". St. Jude Progress Blog - St. Jude Children’s Research Hospital. Retrieved 2020-04-01.{{cite web}}: |first= has generic name (help)[ user-generated source? ]
  10. 1 2 "Gently Used: Can Recycled Microglia Receptors Prevent Plaque? | ALZFORUM". www.alzforum.org. Retrieved 2020-04-01.
  11. ↑ "New Research Discovery - Alzheimer's and Toxicity Pathways". BioSpace. Retrieved 2020-04-01.
  12. ↑ "LANDO Found to be Key to Microglial Clearance of Amyloid-β and Neuroinflammation". Fight Aging!. 2019-07-05. Retrieved 2020-04-01.
  13. ↑ "Pathway discovered that prevents buildup of Alzheimer's protein". www.stjude.org. Retrieved 2020-04-01.
  14. ↑ Heckmann, Bradlee L.; Teubner, Brett J. W.; Boada-Romero, Emilio; Tummers, Bart; Guy, Clifford; Fitzgerald, Patrick; Mayer, Ulrike; Carding, Simon; Zakharenko, Stanislav S.; Wileman, Thomas; Green, Douglas R. (14 August 2020). "Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease". Science Advances. 6 (33): eabb9036. Bibcode:2020SciA....6.9036H. doi:10.1126/sciadv.abb9036. PMC   7428329 . PMID   32851186.
  15. ↑ "Research". Heckmann Lab. Retrieved 2022-08-25.
  16. ↑ "July 24, 2019". UsAgainstAlzheimer's. Retrieved 2020-05-01.
  17. ↑ "Bradlee L. Heckmann | Cell Journalist | Muck Rack". muckrack.com. Retrieved 2020-05-01.
  18. ↑ "LC3-associated endocytosis: guarding against neuroinflammation & neurodegeneration". LabRoots. Retrieved 2020-05-01.
  19. ↑ "Aegean Conferences". www.aegeanconferences.org. Retrieved 2020-05-01.
  20. ↑ Heckmann, Bradlee. "Regulation of microglial induced inflammation by non-canonical autophagy".{{cite journal}}: Cite journal requires |journal= (help)
  21. ↑ "A potential new way of treating Alzheimer's Disease". News-Medical.net. 2020-09-07. Retrieved 2020-09-27.
  22. ↑ Valentin (2022-05-09). "The importance of non-canonical autophagy pathways in Alzheimer's disease pathology and potential therapies". Research Features. Retrieved 2022-08-25.
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