Article

Brain insulin signaling and Alzheimer's disease: current evidence and future directions.

Department of Neuroscience, Uppsala University, Box 593, Husargatan 3, Uppsala, Sweden.
Molecular Neurobiology (Impact Factor: 5.47). 12/2011; 46(1):4-10. DOI: 10.1007/s12035-011-8229-6
Source: PubMed

ABSTRACT Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.

1 Bookmark
 · 
125 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Alzheimer's disease (AD) is a chronic and progressive age-related irreversible neurodegenerative disorder that represents 70% of all dementia with 35 million cases worldwide. Successful treatment strategies for AD have so far been limited, and present therapy is based on cholinergic replacement therapy and inhibiting glutamate excitotoxicity. In this context, role of neuroprotective drugs has generated considerable interest in management of AD. Recently, direct intranasal (IN) delivery of drug moieties to the central nervous system (CNS) has emerged as a therapeutically viable alternative to oral and parenteral routes. IN delivery bypasses the blood-brain barrier by delivering and targeting drugs to the CNS along the olfactory and trigeminal neural pathways which are in direct contact with both the environment and the CNS. In an attempt to understand how neurotherapeutics/nanoparticulate delivery systems can be transported from the nose to the CNS, the present review sets out to discuss the mechanism of transport from nose to brain. The aim of this review is to discuss and summarize the latest findings of some of the major studies on IN drug delivery in AD models, with a focus on the potential efficacy of neuroprotective treatments.
    Journal of Drug Targeting 01/2014; · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also the ability to minimize the potentially hazardous off-target effects. Areas covered: This review covers the role of intranasal insulin therapy for cognitive impairment and neurodegeneration, particularly AD. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The review provides evidence that brain insulin resistance is an important and early abnormality in AD, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy. Expert opinion: Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy and specificity of intranasal insulin therapy.
    Expert Opinion on Drug Delivery 11/2013; · 4.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.
    Psychiatry Research Neuroimaging 01/2014; · 3.36 Impact Factor

Full-text

View
57 Downloads
Available from
May 22, 2014