Type 3 diabetes is sporadic Alzheimer׳s disease: Mini-review
Section snippets
Alzheimer׳s disease and brain glucose starvation
Sporadic Alzheimer׳s disease (AD) is the most common cause of dementia in North America and its high incidence and prevalence rates now constitute an epidemic (de la Monte et al., 2009b). AD diagnosis is based on criteria set by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer׳s Disease and Related Disorders Association (NINCDS/ADRDA) and DSM-IV criteria (Cummings, 2007). Although neuroimaging and biomarker panels begin to facilitate its detection
Insulin and IGF actions in the brain
In the central nervous system (CNS), insulin and IGF signaling pathways play critical roles in cognitive function. Insulin, IGF-1 and IGF-2 polypeptide and receptor genes are expressed in neurons (de la Monte and Wands, 2005) and glial cells (Broughton et al., 2007, Freude et al., 2009, Zeger et al., 2007) throughout the brain; their highest levels are in structures that are heavily targeted by neurodegeneration, particularly AD (de la Monte et al., 2009a, de la Monte and Wands, 2005). Insulin
Evidence of type 3 diabetes (brain insulin and IGF resistance and deficiency) in AD
The concept that AD represents a metabolic disease stemmed from studies showing that deficits in cerebral glucose utilization were present very early in the course of disease (Caselli et al., 2008, Langbaum et al., 2010, Mosconi et al., 2008, Mosconi et al., 2009), either prior to, or coincident with the initial stages of cognitive dysfunction (Hoyer, 2004a, Iwangoff et al., 1980). Deficits in cerebral glucose utilization and energy metabolism worsen with progression of cognitive impairment (
Role of insulin/IGF resistance in brain metabolic dysfunction and oxidative stress in AD
Insulin and IGF signaling regulate glucose utilization, metabolism, and ATP synthesis needed for both homeostasis and dynamic modulation of cellular functions (de la Monte and Wands, 2005, Frolich et al., 1998). Consequently, brain insulin/IGF resistance and deficiency are accompanied by impairments in glucose utilization and disruption of energy metabolism, with attendant increases in oxidative stress, ROS production, DNA damage, and mitochondrial dysfunction, all of which drive pro-apoptosis,
Impaired insulin/IGF signaling and tau pathology in AD
Neurofibrillary tangles and dystrophic neurites are the main neuronal cytoskeletal lesions that correlate with severity of dementia in AD (Duyckaerts et al., 2009, Takashima, 2009). Mechanistically, the microtubule-associated protein, tau, gets hyper-phosphorylated due to inappropriate activation of proline-directed kinases such as GSK-3β. Consequently, tau misfolds and self-aggregates into insoluble fibrillar structures (paired helical filaments and straight filaments) that form
Insulin/IGF resistance and amyloid-beta (AβPP-Aβ) neurotoxicity
AD is associated with dysregulated expression and processing of amyloid precursor protein (AβPP), resulting in the accumulation of neurotoxic AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils (plaques). Increased AβPP gene expression, together with altered proteolysis, leads to accumulations of 40 or 42 amino acid length AβPP-Aβ peptides that can aggregate. In familial AD, mutations in the AβPP, presenilin 1 (PS1), or PS2 genes, and inheritance of the Apoliprotein E ε4 (ApoE-
Potential mechanisms of brain insulin/IGF resistance in neurodegeneration
Although aging is clearly the dominant risk factor for AD, growing evidence suggests that brain insulin/IGF resistance is a major factor contributing to mild cognitive impairment, dementia, and AD (Craft, 2005b, Craft, 2006, de la Monte et al., 2009a, Hoyer et al., 1991, Rivera et al., 2005). Over the past several years, this field of research has greatly expanded due to growing information about the causes and consequences of brain insulin resistance and deficiency in relation to cognitive
Conflict of interest
No conflict of interest to declare.
Contributions
Suzanne M. de la Monte.
Role of funding
Supported by AA11431 and AA12908 from the National Institutes of Health.
Acknowledgment
Supported by AA11431 and AA12908 from the National Institutes of Health.
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2023, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Increasing evidences also reported that insulin/insulin-like growth factor (IGF) signaling is remarkably linked with oxidative stress and may involve in the misbalance of glucose utilization and energy metabolism, which brings production of excessive ROS, DNA damage as well as mitochondrial dysfunction. Consequently stimulating pro-apoptotic, pro-inflammatory and amyloid β-protein cascades and alters many signaling pathways (de la Monte, 2014). Further, the peripheral metabolic chaos reported in type 2diabetes are identical to the anomalies found in brains of patients with AD (Hoyer, 2002).