The cascade of
Alzheimer's disease (AD) neurodegeneration is associated with persistent oxidative stress,
mitochondrial dysfunction, impaired energy metabolism, and activation of pro-death signaling pathways. More recently, studies with human postmortem brain tissue linked many of the characteristic molecular and pathological features of AD to reduced expression of the
insulin and
insulin-like growth factor (IGF) genes and their corresponding receptors. We now demonstrate using an in vivo model of intracerebral
Streptozotocin (ic-STZ), that chemical depletion of
insulin and IGF signaling mechanisms combined with oxidative injury is sufficient to cause AD-type neurodegeneration. The ic-STZ-injected rats did not have elevated
blood glucose levels, and pancreatic architecture and
insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration associated with cell loss,
gliosis, and increased immunoreactivity for p53, active
glycogen synthase kinase 3beta, phospho-tau,
ubiquitin, and
amyloid-beta. Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and
choline acetyltransferase, and increased expression of genes encoding
glial fibrillary acidic protein, microglia-specific
proteins,
acetylcholinesterase, tau, and
amyloid precursor
protein. These abnormalities were associated reduced expression of genes encoding
insulin,
IGF-II,
insulin receptor,
IGF-I receptor, and
insulin receptor substrate-1, and reduced
ligand binding to the
insulin and
IGF-II receptors. These results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing
insulin/IGF functions together with increasing oxidative stress, and support our hypothesis that AD represents a neuro-endocrine disorder associated with brain-specific perturbations in
insulin and IGF signaling mechanisms, i.e. Type 3 diabetes.