Abstract:
Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the
progressive loss of memory and cognitive function along with molecular alterations involving
the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs).
Epidemiological evidence has shown that type II diabetes mellitus (T2DM) is a major risk factor
for the development of AD. Among the shared pathological features of both diseases are
impaired insulin signaling and oxidative stress. However, the exact mechanism of how peripheral
insulin resistance in diabetes may contribute to AD pathology remains largely unknown.
Aim: The aim of the present study is to determine the role of impaired insulin signaling along
with reactive oxygen species (ROS) overproduction in the onset of AD-like pathology in an
animal model of T2DM. We also investigate the potential ameliorative properties of
dapagliflozin (SGLT2 inhibitor) and GKT137833 (dual Nox1/Nox4 inhibitor) on the
Alzheimer’s-like symptoms developed in T2DM.
Methods: Female C57BL/6J mice were used to conduct this study. T2DM was induced using a
combination of high-fat diet and low doses of streptozotocin injections. Treatment groups were
administered with either dapagliflozin (2mg/kg) or GKT (40mg/kg) over a period of 9 weeks.
Cognitive function of the studied mice was assessed using the novel object recognition test and
the spontaneous T-Maze alternation test. To test for sensory dysfunction associated with
diabetes, mechanical and heat hyperalgesia were assessed using Hargreave’s test and the
electronic von Frey. The raised beam walking test was also conducted to detect any motor
dysfunction. At the molecular level, western blots were used to assess the expression of NADPH
oxidase-4 (Nox4), insulin receptor substrate-1 (IRS-1) and Tau phosphorylated at Ser404 in the
hippocampus and prefrontal cortex. RT-PCR was also conducted to study the mRNA levels of
Nox1, IRS-1 and IRS-2. Immunohistochemical staining was performed to detect the deposition
of amyloid-beta plaques and tauS404 and S396 hyperphosphorylation in the brain.
Results: Compared to the control group, type 2 diabetic mice showed sensory, cognitive and
motor dysfunction. Treatment with dapagliflozin and GKT reversed spatial and recognition
memory loss, as well as sensory and motor dysfunction in mice. These observations were
paralleled by the reestablishment of the insulin signaling activity and the inhibition of NADPHdependent
ROS overproduction.
Conclusion: This study reveals a potential neuroprotective role of SGLT2 inhibition as well as
Nox1/Nox4 inhibition and highlights the involvement of insulin resistance and oxidative stress in
the progression of Alzheimer’s-like symptoms associated with T2DM. These findings put
forward a potential novel therapeutic strategy for the treatment of AD.