Brain dysfunction in Alzheimer Disease (AD) has been associated with abnormal production of the amyloid-β (Aβ) peptide. Aβ is generated by proteolytic processing from the amyloid precursor protein (APP). APP is a member of the APP gene family which codes for a small family of essential membrane proteins that are expressed at synapses in the brain.
Intact proteins of the APP family might function at synapses, for example as cell adhesion proteins. The Aβ fragment of APP might also have normal functions as a synaptic signal molecule, so there have been extensive efforts to identify synaptic receptors that can bind Aβ. One such receptor for Aβ is the cellular prion protein (PrPC).
Among the human gene variants that can influence the incidence and progression of AD are:
- presenilin (PS) mutations that alter the rate of production of Aβ and cause AD
- an APP mutation that alters processing of APP by PS and protects against AD
- a common PrPC variant that is associated with rapid progression of AD (see)
Results from experiments that were published in 1998 (see this article) suggested a role for FYN tyrosine kinase in the neurotoxic effects of pathogenic Aβ oligomers. There is also evidence (2009) from experiments using PrPC knockout mice that suggest pathogenic oligomers of Aβ can disrupt normal synaptic function by binding to membrane complexes containing the PrPC protein. Since 2014 (see this article), the lab of Stephen Strittmatter has been investigating the idea that Aβ oligomers can regulate FYN kinase activity by binding to PrPC (or, possibly, other proteins that interact with PrPC) and altering the function of mGluR5 receptors (see the image, above).
2017. A recent article from the Strittmatter lab (Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes) presents evidence for the ability of a drug (a silent allosteric modulator, SAM, BMS-984923) to bind mGluR5 receptors and inhibit neurotoxicity arising from Aβ oligomers.
The mGluR5 receptor-binding drug BMS-984923 is called a “silent allosteric modulator” because it does not block the normal function of mGluR5 receptors to respond to the neurotransmitter glutamate (Glu).
In contrast, conventional inhibitors of mGluR5 receptors (NAMs, see the image, above) disrupt normal glutaminergic synaptic neurotransmission. Results from Strittmatter et al suggest that BMS-984923 might prevent disregulation of FYN kinase, hyperphosphorylation of tau protein and neurotoxicity caused by Aβ oligomers.