Research Models

Atg16LΔWD

Synonyms: Atg16LΔWD, Atg16l1E230, Atg16L1-WD-deficient, Atg16L1-WD knockout

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). Atg16LΔWD mice express a prematurely truncated version of the autophagy protein ATG16L1, missing the WD (tryptophan-aspartate) repeat domain. Microglia cultured from Atg16LΔWD mice show impaired recycling of TREM2, CD36, and TLR4. Initial characterization of a small sample of aged Atg16LΔWD 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 Atg16LΔWD 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 Atg16LΔWD 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 Atg16LΔWD mice.

Gliosis

Microglia in the hippocampi and cortices of Atg16LΔWD 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 Atg16LΔWD mice, compared with wild-type controls.

Neurodegeneration

There were fewer neurons in the hippocampi of Atg16LΔWD 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 Atg16LΔWD mice, compared with wild-type mice.

Behavior

Atg16LΔWD 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

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Plaques

No Data

  • Tangles
  • Synaptic Loss

Plaques

Intracellular and extracellular Aβ deposits, but no dense-core plaques, in 2-year-old mice.

Tangles

No data.

Neuronal Loss

Apparent neuron loss in hippocampi of 2-year-old mice (fewer neurons, increased levels of cleaved caspase-3, and increased numbers of TUNEL-positive neurons).

Gliosis

Microgliosis in the hippocampi of 2-year-old mice.

Synaptic Loss

No data.

Changes in LTP/LTD

Impaired long-term potentiation at CA3-CA1 synapses.

Cognitive Impairment

Deficits in the sucrose preference test, spontaneous alternation in the Y-maze, and novel object recognition test.

Last Updated: 12 Nov 2020

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References

News Citations

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

Paper Citations

  1. . Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease. Sci Adv. 2020 Aug;6(33):eabb9036. Epub 2020 Aug 14 PubMed.
  2. . 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

Papers

  1. . The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes. EMBO J. 2018 Feb 15;37(4) Epub 2018 Jan 9 PubMed.