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Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological data show that the incidence of AD increases with age and doubles every 5 years after 65 years of age. From a neuropathological point of view, amyloid-β-peptide (Aβ) leads to senile plaques, which, together with hyperphosphorylated tau-based neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of AD. Aβ is associated with the formation of reactive oxygen (ROS) and nitrogen (RNS) species, and induces calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions associated with learning and memory. Oxidative stress was found to be associated with type 2 diabetes mellitus (T2DM), which (i) represents another prevalent disease associated with obesity and often aging, and (ii) is considered to be a risk factor for AD development. T2DM is characterized by high blood glucose levels resulting from increased hepatic glucose production, impaired insulin production and peripheral insulin resistance, which close resemble to the brain insulin resistance observed in AD patients. Furthermore, growing evidence suggest that oxidative stress play a pivotal role in the development of insulin resistance and vice versa. This review article provides molecular aspects and the pharmacological approaches from both preclinical and clinical data and interpreted from the point of view of oxidative stress with the aim to highlight progresses in this field.

The clinical symptoms of Alzheimer disease (AD) include a gradual memory loss and subsequent dementia, and neuropathological deposition of senile plaques and neurofibrillary tangles. At the molecular level, AD subjects present overt amyloid b (Ab) production and tau hyperphosphorylation. Ab species have been proposed to overactivate the phosphoinositide3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis, which plays a central role in proteostasis. The current study investigated the status of the PI3K/Akt/mTOR pathway in post-mortem tissue from the inferior parietal lobule (IPL) at three different stages of AD: late AD, amnestic mild cognitive impairment (MCI) and pre-clinical AD (PCAD). Our findings suggest that the alteration of mTOR signaling and autophagy occurs at early stages of AD. We found a significant increase in Ab (1-42) levels, associated with reduction in autophagy (Beclin-1 and LC-3) observed in PCAD, MCI, and AD subjects. Related to the autophagy impairment, we found a hyperactivation of PI3K/ Akt/mTOR pathway in IPL of MCI and AD subjects, but not in PCAD, along with a significant decrease in phosphatase and tensin homolog. An increase in two mTOR downstream targets, p70S6K and 4EBP1, occurred in AD and MCI subjects. Both AD and MCI subjects showed increased, insulin receptor substrate 1, a candidate biomarker of brain insulin resistance, and GSK-3b, a kinase targeting tau phosphorylation. Nevertheless, tau phosphorylation was increased in the clinical groups. The results hint at a link between Ab and the PI3K/Akt/mTOR axis and provide further insights into the relationship between AD pathology and insulin resistance. In addition, we speculate that the alteration of mTOR signaling in the IPL of AD and MCI subjects, but not in PCAD, is due to the lack of substantial increase in oxidative stress.

Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.

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Numerous studies have shown that neuronal lipids are highly susceptible to oxidative stress including in those brain areas directly involved in the neurodegenerative process of Alzheimer’s disease (AD). Lipid peroxidation directly damages membranes and also generates a number of secondary biologically active products (toxic aldehydes)that are capable of easily attacking lipids, proteins, and DNA. Accumulating evidence has demonstrated regionally increased brain lipid peroxidation in patients with AD; however, extensive studies on specific targets of lipid peroxidation-induced damage are still missing. The present study represents a further step in understanding the relationship between oxidative modification of protein and neuronal death associated with AD. We used a proteomics approach to determine specific targets of lipid peroxidation in AD brain, both in hippocampus and inferior parietal lobule, by coupling immunochemical detection of 4-hydroxynonenal-bound proteins with 2-D polyacrylamide gel electrophoresis and MS analysis. We identified 4-hydroxynonenal-bound proteins in the hippocampus and inferior parietal lobule brain regions of subjects with AD. The identified proteins play different biological functions including energy metabolism, antioxidant system, and structural proteins, thus impairing multiple molecular pathways. Our results provide further evidence for the role of lipid peroxidation in the pathogenesis of AD.

DS is the most frequent genetic cause of intellectual disability characterized by the anomalous presence of three copies of chromosome 21. One of the peculiar features of DS is the onset of Alzheimer’s disease neuropathology after the age of 40 years characterized by deposition of senile plaques and neurofibrillary tangles. Growing studies demonstrated that increased oxidative damage, accumulation of unfolded/damaged protein aggregates and dysfunction of intracellular degradative system are key players in neurodegenerative processes. In this study, redox proteomics approach was used to analyze the frontal cortex from DS subjects under the age of 40 compared with age-matched controls, and proteins found to be increasingly carbonylated were identified. Interestingly, our results showed that oxidative damage targets specifically different components of the intracellular quality control system such as GRP78, UCH-L1, V0-ATPase, cathepsin D and GFAP that couples with decreased activity of the proteasome and autophagosome formation observed. We also reported a slight but consistent increase of Aβ 1–42 SDS- and PBS-soluble form and tau phosphorylation in DS versus CTR. We suggest that disturbance in the proteostasis network could contribute to the accumulation of protein aggregates, such as amyloid deposits and NFTs, which occur very early in DS. It is likely that a sub-optimal functioning of degradative systems occur in DS neurons, which in turn provide the basis for further accumulation of toxic protein aggregates. The results of this study suggest that oxidation of protein members of the proteostatis network is an early event in DS and might contribute to neurodegenerative phenomena.