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Lipid Peroxidation Unit

Christopher Ramsden, M.D., Ph.D., Chief

 

Mission

The Lipid Peroxidation Unit leverages expertise in brain lipids and lipoproteins to reveal molecular mechanisms and develop new treatments for age-related diseases, including chronic pain and Alzheimer’s disease.

Background

Dysfunctional lipid metabolism and accelerated lipid peroxidation are hallmarks of aging and many of the most consequential age-associated diseases that collectively rob quality of life and vitality from older Americans.

Approach and Aims

The Unit applies a translational, team science approach—including clinical trials, postmortem studies, advanced immunohistochemical (IHC) methods, synthetic and analytical chemistry, and cellular assays—to achieve the following Aims:

Aim 1: (A) To uncover molecular mechanisms linking dysfunctional lipid and lipoprotein metabolism to neurodegeneration in Alzheimer’s disease, and (B) to identify new mechanism-based biomarkers and therapeutic targets for Alzheimer’s disease in humans.

Aim 2: (A) To reduce the burden of chronic pain by developing and advancing effective, safe diet and drug treatments, and (B) to identify endogenous lipid mediators and molecular mechanisms underlying the pain reduction observed in clinical trials.

Selected Projects and Accomplishments

Alzheimer’s Disease

A new mechanistic paradigm for sporadic Alzheimer’s disease in humans

Our team proposed and provided evidence supporting a new mechanistic paradigm and unifying model for sporadic Alzheimer’s disease (AD) in humans (Fig 1).

ApoER2-Dab1 pathway disruption as an alternative explanation and unifying model for sporadic AD in humans
Fig 1. ApoER2-Dab1 pathway disruption as an alternative explanation and unifying model for sporadic AD in humans. The ApoER2-Dab1 pathway suppresses Tau phosphorylation as part of a four-arm pathway that stabilizes actin, microtubules, and synapses, and delivers essential lipid cargo via lipoprotein internalization.

In AD, pathway disruption at the level of ApoER2 is proposed to destabilize actin, microtubules, and synapses, to disrupt lipoprotein internalization, and to induce the co-accumulation of multiple ApoER2-Dab1 pathway components. 1.

This model, which is supported by evidence gathered from human brain regions that regulate the formation of memories (2) and five regions that degenerate in the earliest stages of AD (1) is attractive because it could help explain the origins and progression of Tau pathology and provides a plausible shared mechanism capable of integrating Tau with other hallmark and emerging AD pathologies (Fig 2).

Multiplex-IHC reveals accumulation of multiple hallmark and emerging pathological markers in the memory circuity in human AD brain.
Fig 2. Multiplex-IHC reveals accumulation of multiple hallmark and emerging pathological markers in the memory circuity in human AD brain. 

Multiple ApoER2-Dab1 pathway components (ApoE, ApoJ, Reelin, Dab1, and phosphorylated versions of P85α, PSD95 and Tau) accumulate together in AD brain. (2)

This ApoER2-Dab1 pathway disruption model reframes hallmark Tau and β-amyloid pathologies as downstream consequences, rather than causal mechanisms, that underlie sporadic AD in humans. This new mechanistic paradigm suggests new leads for biomarkers, therapeutics and prevention.

A potential ‘initiating molecular lesion’ in Alzheimer’s disease

Our team proposed and provided evidence for lipid and lipoprotein peroxidation-induced ApoE receptor-ligand disruption as a specific molecular lesion that could initiate AD pathology in humans 1. This included evidence that: (1) ApoE and ApoE receptors are vulnerable to peroxidation-induced damage, (2) peroxidation modified ApoE accumulates in neuritic plaques; (3) multiple ApoER2-Dab1 pathway components accumulate in the immediate vicinity of neuritic plaques and abnormal neurons in Mild Cognitive Impairment and Alzheimer’s disease (1) (2)

Looking deeper into the Alzheimer’s disease brains with multiplex IHC

Together with Dragan Maric (NINDS), our team co-developed and applied human brain-specific multiplex-IHC panels to enable concurrent labeling of >80 targets in a single Alzheimer’s disease brain section (Figs 2-3).

Multiplex-IHC reveals the complexity and protein composition of peri-vascular plaques in sporadic Alzheimer’s disease brain
Fig 3. Multiplex-IHC reveals the complexity and protein composition of peri-vascular plaques in sporadic Alzheimer’s disease brain.

This human multiplex-IHC platform—which expanded upon pioneering work by Maric et al. in animal models—provides unprecedented spatial, morphological, and cytoarchitectural context for human AD pathologies. We applied these advanced techniques together with traditional single-marker IHC to characterize lipid-related derangements in human brain regions that regulate memory formation2 and five regions that degenerate in the earliest stages of Alzheimer’s disease 1. In current work, we are expanding the platform to include cortical layer-specific markers, subpopulations of excitatory and inhibitory neurons, and additional subtypes of neurites, synapses, and glia.

Phosphorylated PSD95 as a biomarker of synapse disassembly in Alzheimer’s disease

Synapse dysfunction and loss are closely linked to cognitive decline in Alzheimer’s disease. Phosphorylation of the synaptic protein PSD95 causes disassembly of synapses in preclinical models. Our team generated monoclonal antibodies enabling selective detection of phosphorylated forms of PSD95 as promising new mechanism-based biomarkers for Alzheimer’s disease.

Phosphorylated PSD95 accumulates as globular and vacuolar shaped structures within neurons and around plaques in brain tissue.
Fig 4. Phosphorylated PSD95 accumulates in neuritic plaques and abnormal neurons in the hippocampus in Alzheimer’s disease. This image shows that phosphorylated PSD95 accumulates as globular and vacuolar shaped structures within neurons and around plaques in brain tissue.

Mechanisms underlying neurodegeneration in cellular models

Liz Calzada, PhD (postdoctoral fellow) is leading the development of neuron and astrocyte cell culture projects with dual goals of: (1) characterizing toxic effects and protective responses induced by lipid peroxidation products; and (2) characterizing and manipulating lipid and lipoprotein-related signaling pathways.

Chronic Pain

Chronic pain is among the most common and consequential diseases in older adults, and a major source of suffering, disability, social isolation, and societal costs. Available pain treatments are partially effective and limited by side effects that can be particularly problematic in older adults. Chronic pain is also a major risk factor for premature death and dementia, suggesting potential shared mechanisms between pain (or its treatment) and accelerated cognitive decline. The Lipid Peroxidation Unit seeks to uncover biological mechanisms linking lipids to pain, and to leverage this knowledge to develop and advance non-addictive treatments to improve the lives of older adults.

New diet and drug treatments for chronic pain

Testing a new diet-lipid-pain hypothesis in controlled trials

Our team is leading or collaborating on randomized controlled trials testing the clinical and biochemical effects of targeted manipulation of dietary fats that are precursors to lipid mediators of pain. These trials include more than 480 randomized participants, including 350 suffering with pain syndromes that are often refractory to conventional medical management. Accomplishments of this work include (1) The first demonstration that targeted dietary manipulation can decrease frequency and severity of physical pain in humans (published in PAIN3); and (2) confirmation in a larger tightly-controlled trial demonstrating that targeted substrate manipulation decreased physical pain while decreasing use of pain medications (published in The BMJ4 Clinical improvements in both trials were accompanied by alterations in pain mediators derived from dietary fatty acids, supporting plausibility of clinical findings, and providing clues for underlying mechanisms.

Designing and testing new drugs

Lipid Peroxidation Unit members leveraged biochemical insights from human diet-pain studies to design and synthesize two families of ‘diet-mimetic’ drugs that have shown promising anti-inflammatory and analgesic (pain relieving) properties in preclinical pain models. Team members also identified potential new lipid mediators of pain and itch. The long-term goal of these efforts is to develop targeted, effective, non-addictive drugs to treat chronic pain.

Cardiovascular disease

A tweak to the diet-lipid-heart hypothesis?

Our team led the recovery and publication of missing data from two landmark randomized controlled ‘diet-heart’ trials—the Minnesota Coronary Experiment 5 and the Sydney Diet Heart Study 6 that were not fully published by the original investigators. Findings from these two trials contributed to a re-evaluation of the traditional understanding of the diet-heart hypothesis.

Summary

The Lipid Peroxidation Unit conducts research to understand and treat age-related diseases, with an emphasis on the roles of dysfunctional lipid metabolism and accelerated lipid peroxidation. Our work has contributed to new mechanistic paradigms for Alzheimer’s disease, chronic pain and cardiovascular disease, and new interventions for chronic pain.

Selected Publications

Alzheimer’s disease

1. Ramsden CE, Zamora D, Horowitz MS, Jahanipour J, Calzada E, Li X, Keyes GS, Murray HC, Curtis MA, Faull RM, Sedlock A, Maric D. ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease Acta Neuropathol Commun (Dec 13, 2023).

2. Ramsden CE, Keyes GS, Calzada E, Horowitz MS, Zamora D, Jahanipour J, Sedlock A, Indig FE, Moaddel R, Kapogiannis D, Maric D. Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer's Disease in Humans. J Alzheimers Dis. (March 23, 2022).

 

Chronic Pain

3. Ramsden CE, Faurot KR, Zamora D, Suchindran CM, MacIntosh BA, Gaylord S, Ringel A, Hibbeln JR, Feldstein AE, Mori TA, Barden A, Lynch C, Coble R, Mas E, Palsson O, Barrow DA, Mann DJ. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial (PAIN. 2013).

4. Ramsden CE, Zamora D, Faurot KR, MacIntosh B, Horowitz M, Keyes GS, Yuan ZX, Miller V, Lynch C, Honvoh G, Park J, Levy R, Domenichiello AF, Johnston A, Majchrzak-Hong S, Hibbeln JR, Barrow DA, Loewke J, Davis JM, Mannes A, Palsson OS, Suchindran CM, Gaylord SA, Mann JD. Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial (BMJ. 2021).

Cardiovascular disease

5. Ramsden CE, Zamora D, Majchrzak-Hong S, Faurot KR, Broste SK, Frantz RP, Davis JM, Ringel A, Suchindran CM, Hibbeln JR. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73).(BMJ 2016).

6. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM, Hibbeln JR. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis (BMJ. 2013).

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