Therapeutics that enhance SORLA might combat Alzheimer's disease
Alzheimer's disease (AD) is the most common irreversible cause of dementia, accounting for 50-70% of all dementia cases. Of the various genetic risk factors linked to AD, apolipoprotein E (ApoE) is the most prevalent one. The ApoE gene makes an enzyme critical for cholesterol transport. In the central nervous system, ApoE helps transport cholesterol to neurons. Three main ApoE variants exist (E2, E3, and E4), and ApoE4 carriers are prone to high cholesterol and Alzheimer's disease.
SORLA (also known as SORL1 or LR11), a gene that produces a protein that functions as a neuronal ApoE receptor, is also an AD-related genetic risk factor. Lack of SORLA has been suspected to contribute to AD. According to a new study, SORLA provides protection against neurodegeneration, a discovery that would lead to new therapies for the neurodegenerative disorder AD.
The work was conducted by researchers from Sanford Burnham Prebys Medical Discovery Institute (SBP), the University of California in the USA, and Max-Delbrueck-Center for Molecular Medicine in Germany. The results revealed that SORLA interacts with EphA4 and reduces downstream effects of EphA4 signaling in neurons.
EphA4, or EPH receptor A4, is a member of the ephrin receptor subfamily of the protein-tyrosine kinase family. Previous evidence suggests that activation of EphA4 is critical for synaptic dysfunctions in AD, while blockade of EphA4 signaling ameliorates the Aβ-induced synaptic dysfunction in mouse models of AD. Aβ is well-known to contribute to AD progression through its neurotoxic and inflammatory effects.
Further investigation showed that SORLA transgenic mice had reduced EphA4 activation and milder deficits in memory induced by Aβ, compared with wild-type mice. The researchers also analyzed active EphA4 levels in the brains of AD patients, and discovered that "EphA4 activation is inversely correlated with SORLA/EphA4 association."
Collectively, these data suggest that SORLA reduces synaptotoxic EphA4 activation and cognitive impairment associated with Aβ-induced neurodegeneration in AD.
According to co-senior author Prof. Huaxi Xu of SBP, therapeutic agents that increase SORLA levels or enhance its interaction with EphA4 might be used to combat AD. Prof. Xu is focused on identifying the underlying causes of AD at a molecular level, in hopes to find methods to slow or prevent the effects of AD.
Synaptic dysfunction occurs early in the progression of AD and correlates with cognitive impairment. This study adds to the growing body of evidence that inhibiting EphA4 activation may be a new method to attenuate Aβ-induced synaptic dysfunction and subsequent cognitive impairment.
AD affects over 50 million people worldwide, and currently, the devastating disease is basically incurable. The disease not only has deleterious effects on the patients but also have deleterious effects on their families and the whole society.
The study, titled "SORLA attenuates EphA4 signaling and amyloid β–induced neurodegeneration," appears this month in the Journal of Experimental Medicine (JEM).
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