Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer’s APP/PSEN1 mice by gene targeting of diabetes/Alzheimer’s-related Sorcs1

Abstract

IntroductionInsulin resistance and type 2 diabetes mellitus (T2D) are associated with increased risk for cognitive impairment, Alzheimer’s disease (AD) and vascular dementia. SORCS1 encodes a protein-sorting molecule genetically linked to both T2D and AD. The association of SORCS1 with both AD and T2D is sexually dimorphic in humans, with both disease associations showing more robust effects in females. Based on published evidence that manipulation of the mouse genome combining multiple genes related to cerebral amyloidosis, to T2D, or both, might provide novel mouse models with exacerbated amyloid and/or diabetes phenotypes, we assessed memory, glucose homeostasis, and brain biochemistry and pathology in male and female wild-type, Sorcs1 -/-, APP/PSEN1, and Sorcs1 -/- X APP/PSEN1 mice.ResultsMale mice with either the APP/PSEN1 or Sorcs1 -/- genotype displayed earlier onset and persistent impairment in both learning behavior and glucose homeostasis. Unlike prior examples in the literature, the behavioral and metabolic abnormalities in male mice were not significantly exacerbated when the two disease model mice (Sorcs1 -/- models T2D; APP/PSEN1 models AD) were crossed. However, female Sorcs1 -/- X APP/PSEN1 mice exhibited worse metabolic dysfunction than Sorcs1 -/- knockout mice and worse memory than wild-type mice. The deletion of Sorcs1 from APP/PSEN1 mutant mice led to no obvious changes in brain levels of total or oligomeric amyloid-beta (Aβ) peptide.ConclusionsIn general, unexpectedly, there was a trend for gene targeting of Sorcs1-/- to partially mitigate, not exacerbate, the metabolic and amyloid pathologies. These results indicate that crossing AD model mice and T2D model mice may not always cause exacerbation of both the amyloidosis phenotype and the metabolic phenotype and highlight the unexpected pitfalls of creating mixed models of disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0282-y) contains supplementary material, which is available to authorized users.

Deficiency of TYROBP, an adapter protein for TREM2 and CR3 receptors, is neuroprotective in a mouse model of early Alzheimer’s pathology

“…A11 and OC oligomer strains are not consistently neurotoxic. As reported above and in one of our previous studies [ 41 ], we noted sex differences in Aβ and oligomer levels suggesting an earlier progression of the disease in female than male APP/PSEN1 mice.…”

“…Immunohistochemical and biochemical characterization were performed as previously described [ 40 , 41 , 44 , 76 ]. For biochemical analysis, hemibrains were processed via differential detergent solubilization to produce TBS-soluble, Triton-X-soluble, and formic-acid soluble Aβ fractions.…”

“…In the Tyrobp -null mouse, there is a deletion of exons 3 and 4 resulting in loss of function of the TYROBP protein by deletion of the transmembrane region and part of the cytoplasmic region including the first tyrosine of the ITAM motif [ 2 ]. The APP/PSEN1 mouse model [ 29 ] expresses APP KM670/671NL /PSEN1 Δexon9 in neurons and accumulates in the interstitial spaces of the brain fibrillar amyloid that goes on to form typical amyloid plaques accompanied by neuritic dystrophy, age-dependent synaptic loss without neuronal loss, and abnormalities in spatial memory [ 25 , 29 , 40 , 41 ]. Since TYROBP expression is increased in the LOAD brain [ 86 ], we hypothesized that the APP/PSEN1 phenotype may be improved in the presence of reduced TYROBP levels.…”

Type 2 diabetes mellitus might be a risk factor for mild cognitive impairment progressing to Alzheimer’s disease

“… 5 Type 2 diabetes mellitus (T2DM) might also be a potential risk for MCI progressing into AD, by inducing vascular dysfunction and oxidative and inflammatory stress. 6 Many cognitive functions, such as learning and memory, mental flexibility, and mental speed, have also been proved to be impaired in patients with T2DM. 7 Some epidemiological studies demonstrated that T2DM was a risk factor for developing cognitive impairment and dementia, including AD.…”

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

“…Immunohistochemical and biochemical characterization were performed as previously described (3,(189)(190)(191)(192). For biochemical analysis, hemibrains were processed via differential detergent solubilization to produce TBS-soluble, Triton-X-soluble, and formic-acid soluble Aβ fractions.…”