Fight Aging!

Alzheimer's disease is characterized by the presence of protein aggregates in the brain. These are misfolded and altered versions of proteins that can act as seeds for solid deposits to form and spread in the brain. These deposits are surrounded by a halo of toxic biochemistry that harms and eventually kills neurons. Amyloid-β aggregates are present in the early stages of the condition, while tau aggregates cause much greater harm and cell death in the later stages.

Alzheimer's disease is also an inflammatory condition, however, in which chronic inflammation and altered behavior of the central nervous system immune cells known as microglia is clearly very influential. The interaction between amyloid-β, tau, and inflammation is somewhat debated. One view is that early amyloid-β aggregation causes microglia to become dysfunction and inflammatory, and this behavior generates an environment of chronic inflammation that results in tau aggregation. Alternatively, amyloid-β accumulation may just be a side-effect of persistent infections that produce chronic inflammation in the brain. Both of these options might be true to varying degrees in different patients. It is quite challenging to pick apart the mechanisms of early Alzheimer's in humans, as it isn't feasible to open up large numbers of living brains to take a look at their biochemistry.

Today's research materials add support for the more complex picture of differing contributions and interactions of amyloid-β and inflammation from individual to individual. The scientists involved suggest that only some amyloid-β plaques will trigger inflammation, those in which the amyloid-β is mixed in with nucleic acids. No doubt the propensity for plaques to be so structured varies from individual to individual for reasons that have yet to be explored. This is all quite interesting, but it still runs into the problem that removal of amyloid-β doesn't seem to help Alzheimer's patients, even when accomplished early. That one point is the largest obstacle to any theory that involves amyloid-β generating chronic inflammation sufficient to advance the disease processes.

Connecting interferon, neuroinflammation and synapse loss in Alzheimer's disease

Amyloid plaques in the brains of people with Alzheimer's disease have a heterogeneous composition; for instance, some may also contain sugars, lipids, or nucleic acids. Previously, researchers found that amyloid fibrils with nucleic acids, but not those without them, triggered immune cells in the blood to produce type 1 interferon (IFN). IFN is a potent cytokine produced when immune cells sense nuclei acids, such as those that come from viral particles, in their environment. IFN triggers a beneficial inflammatory response that is the first line of defense against viral infections.

Researchers found that the same mouse brains that had amyloid plaques with nucleic acids also showed a molecular signature mimicking an antiviral IFN response. Further experiments revealed that nucleic acids in the plaques activated brain microglia, which produced IFN that in turn triggered a cascade of inflammatory reactions that led to the loss of synapses, the junctions between neurons through which they communicate. Synapse loss is a key part of neurodegeneration and can lead to memory loss and eventually dementia.

The accumulation of amyloid plaques in human brains is known to poorly correlate with the severity or duration of dementia. There are people without signs of dementia who harbor significant amounts of both amyloid plaques and tau tangles in their brains, but remarkably lack the robust microglial activation and inflammatory response that is associated with loss of synapses and neurons. "Our findings in mouse models suggest that it is plausible that plaques that accumulate in Alzheimer's disease patients and those in non-demented individuals differ in their content of nucleic acids. It is thus of great interest to examine more closely the molecular constituents of amyloid plaques in the brains of cognitively resilient individuals and compared them to those of Alzheimer's disease cases."

Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease

Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we have demonstrated a potent IFN immunogenicity of nucleic acid (NA)-containing amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected in the brains of multiple murine Alzheimer disease (AD) models, a phenomenon also observed in wild-type mouse brain challenged with generic NA-containing amyloid fibrils.

In vitro, microglia innately responded to NA-containing amyloid fibrils. In AD models, activated ISG-expressing microglia exclusively surrounded NA-positive amyloid β plaques, which accumulated in an age-dependent manner. Brain administration of recombinant IFNβ resulted in microglial activation and complement C3-dependent synapse elimination in vivo. Conversely, selective IFN receptor blockade effectively diminished the ongoing microgliosis and synapse loss in AD models. Moreover, we detected activated ISG-expressing microglia enveloping NA-containing neuritic plaques in post-mortem brains of AD patients. Gene expression interrogation revealed that IFN pathway was grossly upregulated in clinical AD and significantly correlated with disease severity and complement activation.