Species: Mouse
Genes: Atg16l1
Modification: Atg16l1: Knock-Out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Mixed 129, C57BL/6
Availability: Mice are available from Ulrike Mayer or Thomas Wileman.

Summary

In addition to their roles in canonical autophagy, some protein components of the autophagy machinery are involved in recycling cell-surface receptors in microglia (see Jun 2019 News). Atg16L^ΔWD mice express a prematurely truncated version of the autophagy protein ATG16L1, missing the WD (tryptophan-aspartate) repeat domain. Microglia cultured from Atg16L^ΔWD mice show impaired recycling of TREM2, CD36, and TLR4. Initial characterization of a small sample of aged Atg16L^ΔWD mice revealed AD-like features, including Aβ accumulation, tau hyperphosphorylation, neuroinflammation, neuron loss, and cognitive deficits (Heckmann et al, 2020). Variants in ATG16L1 have not yet been associated with the risk of AD, and it is unclear whether these mice actually model spontaneous AD or merely mimic the disease.

The following descriptions refer to 2-year-old mice.

Aβ accumulation

Immunohistochemistry revealed abundant intracellular and extracellular Aβ deposits throughout the hippocampi and cortices of Atg16L^ΔWD mice, but no dense-core plaques; these deposits were nearly absent from their wild-type littermates. Biochemical studies were consistent with the immunohistochemical findings: the brains of Atg16L^ΔWD mice contained elevated levels of soluble, but not insoluble, Aβ.

Tau hyperphosphorylation

Increased levels of hyperphosphorylated tau were found both immunohistochemically and biochemically in the hippocampi and cortices of Atg16L^ΔWD mice.

Gliosis

Microglia in the hippocampi and cortices of Atg16L^ΔWD mice adopted an amoeboid morphology and increased their expression of Iba1. Levels of the proinflammatory cytokines interleukin-1β,  (IL-1β), interleukin-6, and tumor necrosis factor-α  were elevated in the brains of Atg16L^ΔWD mice, compared with wild-type controls.

Neurodegeneration

There were fewer neurons in the hippocampi of Atg16L^ΔWD mice than wild-type mice. Increased levels of cleaved caspase-3 and increased numbers of TUNEL-positive neurons in the mutant mice suggest that the smaller number of neurons is due to cell loss.

Electrophysiology

Long-term potentiation at CA3-CA1 synapses was impaired in brain slices from Atg16L^ΔWD mice, compared with wild-type mice.

Behavior

Atg16L^ΔWD mice exhibited cognitive deficits, assayed using the sucrose preference test, spontaneous alternation in the Y-maze, and novel-object-recognition test.

Modification Details

Two premature stop codons were introduced after the codon for E230, in exon 6 of the Atg16L gene (Rai et al., 2019).

Phenotype Characterization

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

References

News Citations

1. Gently Used: Can Recycled Microglia Receptors Prevent Plaque? 28 Jun 2019

Paper Citations

1. Heckmann BL, Teubner BJ, Boada-Romero E, Tummers B, Guy C, Fitzgerald P, Mayer U, Carding S, Zakharenko SS, Wileman T, Green DR. Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease. Sci Adv. 2020 Aug;6(33):eabb9036. Epub 2020 Aug 14 PubMed.
2. Rai S, Arasteh M, Jefferson M, Pearson T, Wang Y, Zhang W, Bicsak B, Divekar D, Powell PP, Naumann R, Beraza N, Carding SR, Florey O, Mayer U, Wileman T. The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis. Autophagy. 2019 Apr;15(4):599-612. Epub 2018 Nov 7 PubMed.

External Citations

1. Ulrike Mayer
2. Thomas Wileman

Further Reading