Uncovering Central and Peripheral Pain Mechanisms in Alzheimer’s Disease

Student thesis: Doctoral ThesisDoctor of Philosophy


Pain is a clinical issue in neurodegenerative diseases since the risk of chronic pain increases with age-related comorbidities in the elderly and largely impacts one’s quality of life. Alterations in pain perception and processing are documented in individuals with Alzheimer’s Disease (AD) who often report pain less than healthy controls. However, adequate assessment of pain in AD is hindered by patients’ inability to communicate.
Current treatment, when it occurs, relies heavily on paracetamol and fentanyl patches, which may induce several side effects in these patients. As such, a better understanding of nociceptive mechanisms under AD neurodegenerative conditions would identify pathways and delineate new avenues for analgesic strategies.

Aim of this thesis was to investigate alterations within the nociceptive pathways, under neuropathic pain conditions. Using the TASTPM transgenic mouse model of AD, we focussed on neuronal/immune changes at the site of injury in sciatic nerve, dorsal horn of spinal cord and brainstem in concomitance to the development of mechanical hypersensitivity (allodynia) following peripheral nerve injury.

This thesis shows evidence for attenuation of neuropathic allodynia in TASTPM mice for up to 21 days after peripheral nerve injury compared to wild-type (WT) mice. Such an alteration is linked with an increased peripheral and central opioidergic signalling in TASTPM mice which is not observed in WT mice. Specifically, administration of naloxone hydrochloride, a CNS- penetrant opioid antagonist, exacerbated mechanical allodynia in injured TASTPM mice and induced mechanical hypersensitivity up to levels observed in injured WT mice. Concomitant with these behavioural results, in TASTPM dorsal horn of the spinal cord, we observed higher expression of endogenous inhibitory peptides such as enkephalins and less severe microgliosis compared to WT. All together, these data implicate that in AD mice, a dysfunction of the opioidergic system contributes to the attenuated mechanical allodynia and modulates central sensitisation mechanisms such as microgliosis.

In addition to an increase of the central opioidergic tone, here we provide evidence for changes in the peripheral opioidergic system, likely mediated by immune cells.

Specifically, administration of a peripheralized opioid antagonist, naloxone methiodide, exacerbated neuropathic allodynia in TASTPM, which displayed a lower number of blood classical monocytes and higher number of macrophages at the site of nerve injury compared to WT. Since such macrophages acquired a CD206+/MHCII- phenotype we speculated that they were likely involved in anti-nociceptive effects at the site of injury.
We demonstrate in vitro that TASTPM bone marrow derived macrophages (BMDMs) perform efficient phagocytosis of myelin extracts containing amyloid precursor protein, acquire CD206+/MHCII- phenotype, upregulate mRNA expression of proenkephalin (PENK) and accumulate enkephalins in the culture media.

These data suggest a disrupted opioidergic tone in TASTPM mice, which followed by peripheral nerve injury, is mediated by peripheral immune cells. Our data show that the latter is mediated by the TASTPM immune signature observed both at the injury site and
in bloodstream.

Taken together, this thesis delineates mechanisms underlying alterations in pain processing in AD conditions, but more importantly, it highlights the need to re-evaluate current analgesic treatments with opioids, such as the prescription of fentanyl dermal patches in people with AD.
Date of Award1 Sept 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMarzia Malcangio (Supervisor)

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