Diabetes–like mechanism of Alzheimer disease and prevention of dementia in the elderly people

Abstract

Alzheimer disease (AD) is a major dementia. Toxicity of amyloid–β protein (Aβ), especially Aβ42 oligomers, is considered important in the AD pathogenesis. Alternatively, the diabetes mellitus (DM)–like mechanism is suggested in AD brain, and AD is called as ‘type 3 diabetes’. We induced insulin deficiency (type 1 DM) via injection of streptozotocin (STZ) or insulin resistance (type 2 DM) via high fructose diet (HFuD) in 3xTg–AD mice. Both type DM accelerated accumulation of Aβ42 and hyper–phosphorylated tau protein, causing co–aggregation of them in neurons. Two insulin signaling–related molecules, phosphorylated Akt and phosphorylated GSK–3β, decreased in the STZ and HFuD mice brain, indicating impairment of the insulin signaling. In addition, microglia were activated and proliferated in the STZ and HFuD mice, indicating the exacerbation of neuroinflammation. Thus, peripheral DM may enhance the AD pathology.

Previously, we have reported apomorphine (APO) as a novel drug to promote degradation of the intraneuronal Aβ42 improving insulin resistance of neurons in the 3xTg–AD mice brain. In fact, APO treatment counteracted the inhibitory effects of Aβ peptides on insulin signaling of the cultured Neuro2a cells. Thus, APO may activate PI3K–Akt pathway in the AD neurons and microglia, contributing to the cure of AD.

To consider the prevention of AD, it is noted that dementia, DM and sarcopenia may interact with each other. We presume that the advanced glycation end–products (AGEs), which are known as the age– and DM–related biomarker, may be the key factor among those three diseases. We have reported that dermal AGEs may correlate with the prevalence of mild cognitive impairment as well as a useful biomarker for sarcopenia in men. Thus, life style and supplements that may inhibit the AGEs accumulation may be beneficial for the prevention of AD. We are investigating the collagen peptide as a preventive supplement for atherosclerosis and cognitive decline in the elderly people.