Though it carries nary a human transgene, a new mouse model developed many of the hallmark features of Alzheimer’s disease, according to a study published August 14 in Science Advances.
Mice deficient in the WD domain of the autophagy protein Atg16L1 accumulated Aβ, phosphorylated tau in the brain, developed neuroinflammation and neurodegeneration, and had memory loss. In the mice, cells struggled to perform a newly discovered type of endocytosis, called LANDO, which helps microglia recycle cell-surface receptors, including TREM2. Researchers led by Douglas Green, St. Jude’s Children’s Hospital, Memphis, Tennessee, reported that an inflammasome inhibitor not only quelled neuroinflammation in these knockout mice, but lessened tau phosphorylation, spared neurons, and assuaged memory deficits.
Atg16L-WD knockout mice develop clumps of Aβ, neuroinflammation, and tau phosphorylation. Neuronal loss, synaptic deficits, and learning/memory loss ensue. Blocking inflammation corrects all but the Aβ buildup.
The findings underscore the nexus of endocytosis and neuroinflammation [1] in AD. Even so, some commentators questioned if the knockouts truly model AD, which unfolds over decades. “Additional work is required to determine whether the authors have identified an exciting disease-relevant pathway or a genetic alteration that results in similar downstream phenotypes,” wrote Joseph Lewcock, Kate Monroe, and Lesley Kane from Denali Therapeutics, South San Francisco. Genetic studies have not, thus far, associated loss of the Atg16L1 WD domain with risk of AD.
Read the full article on the Alz Form – Can Loss of a Single Protein Domain Cause ‘Alzheimer’s’ in Mice? [2]