Researchers have demonstrated that enhancing myelin renewal in the brains of transgenic APP/PS1 mouse models of Alzheimer's disease (AD) can improve their task-related hippocampal activity.
"To the best of our knowledge, this is the first study to show that enhancing myelin renewal can alleviate AD-related cognitive impairment," said study leader Feng Mei, a professor in the Department of Histology and Embryology at Third Military Medical University (TMMU).
The new study's findings collectively suggest that enhancing myelin renewal represents a promising therapeutic approach to alleviate AD-related cognitive impairment, the authors reported in the June 8, 2021, edition of Neuron.
Although the FDA approved Aduhelm (aducanumab; Biogen) as the first supposedly disease-modifying treatment for AD, whether the drug is actually effective remains highly controversial.
AD thus remains a largely untreatable age-related neurodegenerative disease characterized by beta-amyloid (Abeta) plaque accumulation and progressive cognitive decline and dementia.
AD-related cognitive impairment is mainly due to neuronal dysfunction and degeneration, but significant disruptions in glial function have also been reported, as have been changes in AD patients' white matter.
White matter comprises axons and myelin, the fatty sheath produced by oligodendrocytes, which is critical for neuronal signaling.
However, it remains unclear whether white matter abnormalities actively contribute to AD symptoms and/or progression, or are secondary to neuronal degeneration.
Mature oligodendrocytes and myelin are mostly stable in adult and aging brains, but recent studies have shown that new myelin is continuously generated via oligodendrocyte precursor cell (OPC) differentiation.
This ongoing addition of oligodendrocytes and myelin has been demonstrated to be required for various cognitive tasks, including the preservation of spatial memory.
Myelin degeneration increases with age, contributing to declining cognitive function in aged mice and suggesting altered myelin dynamics may at least partially underlie AD cognitive deficits.
Moreover, evidence from multiple studies implies that myelin and oligodendroglia are significantly altered in AD-related pathology.
For example, single-cell transcriptomic analyses have shown gene expression changes in oligodendrocyte lineage cells from early-stage AD patient brains, while brain myelin abnormalities have been identified in AD models.
For example, Abeta deposition causes demyelination and senescence-like changes in OPCs, while OPC proliferation is increased in transgenic AD mouse brains, suggesting aberrant myelin degeneration and remyelination.
Therefore, understanding AD-related myelin changes may require genetic cell-lineage tracing of the fate of pre-existing and newly formed myelin over time.
In their new Neuron study, the authors characterized myelin generation and loss dynamics in APP/PS1 mice, which revealed an accelerated degeneration of pre-existing myelin sheaths and increased oligodendrogenesis and myelination in the mouse brains, resulting in overall myelin loss.
"The overall myelin loss in the APP/PS1 brains was probably due to both insufficient myelin renewal, together with accelerated degeneration of pre-existing myelin," noted Mei.
Moreover, "the densities of pre-existing myelin in the 13-month-old APP/PS1 mouse cortex and hippocampus were decreased by nearly one-third, compared to age-matched wild-type (WT) controls."
"This myelin degeneration thus seems to be age-related, but the exact mechanisms are unknown," Mei told BioWorld Science.
"One possibility is that soluble Abeta or Abeta expression in the oligodendrocyte may damage myelin internodes in the central nervous system (CNS), as the literature has shown that demyelination could precede Abeta plaque formation."
Importantly, enhancing myelin renewal by genetically deleting the muscarinic M1 receptor (M1R) in OPCs, or by treatment with the pro-myelinating clemastine, were both shown to significantly improve memory-related task performance of the mouse AD models.
"M1R deletion significantly increased endogenous myelinogenesis, which consequently improved memory capacity in the APP/PS1 AD mouse models," said Mei.
"Clemastine is a first-generation antihistamine for the symptomatic treatment of allergies in the clinic, which also exhibits antimuscarinic properties and can efficiently penetrate the blood-brain barrier."
These interventions improved memory-related task performance "using water maze and novel object recognition to assess memory capacity," said Mei.
Genetically or pharmacologically enhancing myelin renewal were further shown to increase occurrence and peak frequency of hippocampal sharp wave ripples (SPW-Rs).
"Hippocampal SPW-Rs are transient high-frequency signaling oscillations that occur during 'offline' states, such as sleep, which are thought to be critical for memory consolidation and which are impaired in the [APP/PS1] mouse model," explained Mei.
Therefore, "their increased occurrence and frequency reflect improvement in hippocampal physiology via enhanced myelinogenesis in the AD mouse model," he said.
These findings demonstrate the potential of enhancing myelination as a therapeutic strategy to improve AD-related cognitive impairment and have implications for AD treatments.
"Previous studies have identified a number of potent myelination-enhancing compounds using high-throughput screening approaches," noted Mei.
"Among these, several FDA-approved drugs, notably clemastine and the selective estrogen receptor modulator bazedoxifene, have been shown using in vivo experiments to be effective in promoting myelination," he said.
"These FDA-approved candidate drugs can probably be modified and repurposed for promoting myelination in AD patients, although it is first essential to verify their safety and efficacy for treating AD in humans."
In the meantime, said Mei, "we would like to investigate the molecular mechanisms underlying accelerated myelin degeneration in AD brains, and develop strategies to prevent myelin from degeneration."