One component of most neurodegenerative diseases is that classes of immune cells resident in the brain adopt disruptive, inflammatory behaviors. This is a reaction in some way to growing levels of damage in the form of aggregated proteins, such as amyloid-β and tau in Alzheimer's disease, but it isn't a helpful reaction. It makes the overall situation worse, producing greater dysfunction in the necessary operations of brain cells. Reducing this immune failure should help to slow disease progression even in the absence of effective ways to remove the protein aggregates - though that will have to happen as well in order to produce some form of cure. The research here ties into SENS views of the causes of aging and age-related disease, in that failure of lysosomes in immune cells is implicated: lysosomes are responsible for recycling cellular waste and damaged components, but with age they become dysfunctional for various reasons. That is problematic in any cell, but particularly so in immune cells that are responsible for gathering and destroying metabolic waste materials from the cellular environment.
Microglia normally gobble up and break down amyloid-β (Aβ). However, in Alzheimer's disease (AD), an altered inflammatory state causes them to stop clearing the aggregated peptide. How does this happen, and can it be stopped? Researchers blame the microglial enzyme RIPK1, and believes that blocking it may help return microglia to their normal state. The kinase appears to set off transcriptional changes that cripple the microglial lysosome system. The cells start producing new gene products, some characteristic of the recently identified disease-associated microglia (DAM) surrounding plaques in AD model mice. Genetically deleting or pharmacologically inhibiting RIPK1 both sped up Aβ clearance and improved memory in an AD mouse model. The findings lay the groundwork for a new treatment for AD, and, since RIPK1 has been implicated in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), for those diseases as well.
"It's the first paper that shows blocking RIPK1 alleviates the inflammatory response, reduces plaque, and improves behavior in AD mice. It points out directly the beneficial effects of inhibiting RIPK1 for the treatment of multiple diseases characterized by inflammation and cell death. Microglial lysosome biology is poised to become the next hot topic in Alzheimer's research. A lot of recent data are pointing to failure of the lysosome in microglia and other innate immune cells as the problem in AD, and rebalancing that as the way forward."
RIPK1, short for Receptor-interacting protein 1 kinase, gets induced in response to the inflammatory signals tumor necrosis factor (TNFa) and ligands of the toll-like receptor (TLR) family. It causes an inflammatory response, controls inflammation-induced cell death (necroptosis), and leads to some forms of apoptosis. The researchers first peered into postmortem human brains and found more phosphorylated RIPK1 in slices from AD patients than controls. This implied that the kinase was activated in the disease. That RIPK1 co-localized with microglial markers suggested that it was expressed primarily in these cells.
What did the kinase do? The authors tested this in APP/PS1 mice by adding to their drinking water a RIPK1 inhibitor the group had previously developed called necrostatin-1 (Nec-1s). After a month, the treated mice had fewer plaques and less soluble and insoluble Aβ in the brain. What's more, whereas five-month-old APP/PS1 mice scurried around an open field in a hyperactive state, a month of Nec-1s treatment calmed them down. The researchers also examined spatial memory with a T-shaped water maze, where mice are trained to find a hidden platform at the end of one arm, then retrained to find it in another. At five months, APP/PS1 mice had trouble learning a new platform location, but a month of Nec-1s restored their performances to match those of wild-type mice.
How does a microglial kinase do this? The researchers added Aβ1-42 to microglia isolated from wild-type mice and mice lacking the kinase. Wild-type cells bumped up production of the inflammatory cytokines TNFa and IL6, mutant cells less so. Wild-type microglia pretreated with Nec-1s also produced less TNFα and IL6. Intriguingly, microglia lacking RIPK1 action better digested synthetic Aβ1-42 oligomers. What whetted their appetites? Analyzing the microglial transcriptomes, reserchers found that one of the proteins upregulated by RIPK1 was cystatin F. Encoded by the Cst7 gene, cystatin F inhibits the endosomal/lysosomal system responsible for breaking down unwanted proteins and other metabolic waste.