Abstract
BackgroundThe pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau aggregation in AD remain elusive. The incidence of AD is increased in patients with type 2 diabetes (T2DM), which is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. However, the molecular mechanisms bridging AD and T2DM remain unknown.MethodsWe first examined the presence of IAPP in the neurofibrillary tangles of AD patients. Then we tested the effect of IAPP on tau aggregation. The biochemical and biological characteristics of the IAPP-tau fibrils were tested in vitro. The seeding activity and neurotoxicity of the IAPP-tau fibrils were confirmed in cultured neurons. Lastly, the effect of IAPP on tau pathology and cognitive impairments was determined by injecting the IAPP-tau fibrils and IAPP fibrils into the hippocampus of tau P301S mice.ResultsWe found that IAPP interacts with tau and accelerates the formation of a more toxic strain, which shows distinct morphology with enhanced seeding activity and neurotoxicity in vitro. Intrahippocampal injection of the IAPP-tau strain into the tau P301S transgenic mice substantially promoted the spreading of tau pathology and induced more severe synapse loss and cognitive deficits, when compared with tau fibrils. Furthermore, intracerebral injection of synthetic IAPP fibrils initiated tauopathy in the brain of tau P301S transgenic mice.ConclusionsThese observations indicate that IAPP acts as a crucial mediator of tau pathology in AD, and provide a mechanistic explanation for the higher risk of AD in individuals with T2DM.
Highlights
The pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer’s disease (AD)
islet amyloid polypeptide (IAPP) interacts with tau in human AD brain To examine whether IAPP participates in tau pathology in AD, we immunostained IAPP in hippocampal brain slides from AD patients and age-matched controls
We found abundant IAPP signals in AD brains, which were hardly detected in age-matched control brains (Fig. 1a, b, Table S1)
Summary
The pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer’s disease (AD). The molecular mechanisms mediating tau aggregation in AD remain elusive. The incidence of AD is increased in patients with type 2 diabetes (T2DM), which is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. T2DM is characterized by the aberrant aggregation and deposition of the islet amyloid polypeptide (IAPP), which leads to the progressive degeneration of pancreatic islet β-cells [10, 11]. Mature IAPP is a peptide consisting of 37 amino acids, which is derived by proteolytic cleavage of the islet amyloid precursor protein. It is produced by pancreatic β-cells and co-released with insulin in response to high glucose levels [12]
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