Evidence for Viral Infection and Inflammation in Familial Alzheimer's Brains
Familial Alzheimer's disease has an earlier onset in comparison to the sporadic Alzheimer's present in much of the population, and is connected to specific variants in genes associated with amyloid-β metabolism. In some cases that means one has to be careful of drawing conclusions based on studies of familial Alzheimer's. Today's research materials note the discovery of viral infection and signs of inflammatory dysfunction in the brains of familial Alzheimer's patients. These patients are likely more vulnerable to the consequences of viral infection, such as increased generation of amyloid-β in its antimicrobial peptide role, but there is little reason to believe that they are more vulnerable to suffering persistent infections than the rest of the population.
There is an ongoing debate in the research community regarding whether or not Alzheimer's is driven in large part by persistent viral infection, such as by herpesviruses. The mechanisms look plausible, and a major role for infection status might go some way towards explaining why only some people go onto develop Alzheimer's disease. The epidemiological data for the role of viral infection is conflicted, but recent studies suggest that combinations of viruses might be required to cause issues, rather than just one infectious agent. Antiviral treatment has been shown in some studies to reduce Alzheimer's risk.
Olfactory Viral Inflammation Associated with Accelerated Onset of Alzheimer's disease
Researchers focused on the olfactory tract, olfactory bulb, and the hippocampus, the area of the brain which manages memory and learning. They examined messenger RNA in the brain tissue of six individuals who had Familial Alzheimer's disease (FAD) and tissue from a control group without AD. They found signatures of viral infection in the olfactory bulbs of the FAD group and inflammation in the olfactory tract which carries information to the hippocampus. They also discovered altered myelination in the olfactory tract. Myelin is a protective fatty layer around nerves that allows electrical impulses to move quickly and smoothly. If it's damaged, signaling stalls.
"These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to the acceleration of FAD progression. The whole olfactory pathway goes to the hippocampus. If you decrease the signaling along that pathway then you get less signaling to the hippocampus. If you don't use it, you lose it. Our hypothesis is that some viruses accelerate Alzheimer's disease."
Alzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation.
Compared to control, FAD OT had increased immunostaining for β-amyloid (Aβ) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.