Rosiglitazone and Pioglitazone for the Treatment of Alzheimer's Disease

Miller, Benjamin; Willett, Kristine C.; Desilets, Alicia R

doi:10.1345/aph.1q238

Cited by 108 publications

(70 citation statements)

References 25 publications

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“…However another small study failed to observe improvements in cognitive symptoms in patients with Alzheimer's [90]. While a randomized clinical trial failed to demonstrate efficacy of rosiglitazone to improve symptoms in Alzheimer's disease [91], larger trials are necessary to clarify the efficacy of pioglitazone to improve cognitive symptoms in Alzheimer's disease [92].…”

Section: Neuroprotective Effects Of Ppargamma Agonistsmentioning

confidence: 99%

Neuroprotection by dietary restriction and the PPAR transcription complex

Mobbs

Moreno

Kim

et al. 2012

Translational Neuroscience

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Although the pathophysiology of neurodegenerative diseases is distinct for each disease, considerable evidence suggests that a single manipulation, dietary restriction, is strikingly protective against a wide range of such diseases. Thus pharmacological mimetics of dietary restrictions could prove widely protective across a range of neurodegenerative diseases. The PPAR transcription complex functions to re-program gene expression in response to nutritional deprivation as well as in response to a wide variety of lipophilic compounds. In mammals there are three PPAR homologs, which dimerize with RXR homologs and recruit coactivators Pgc1-alpha and Creb-binding protein (Cbp). PPARs are currently of clinical interest mainly because PPAR activators are approved for use in humans to reduce lipidemia and to improve glucose control in Type 2 diabetic patients. However, pharmacological enhancement of the activity of the PPAR complex is neuroprotective across a wide variety of models for neuropathological processes, including stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Conversely activity of the PPAR transcriptional complex is reduced in a variety of neuropathological processes. The main mechanisms mediating the neuroprotective effects of the PPAR transcription complex appear to be re-routing metabolism away from glucose metabolism and toward alternative subtrates, and reduction in inflammatory processes. Recent evidence suggests that the PPAR transcriptional complex may also mediate protective effects of dietary restriction on neuropathological processes. Thus this complex represents one of the most promising for the development of pharmacological treatment of neurodegenerative diseases.

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Section: Neuroprotective Effects Of Ppargamma Agonistsmentioning

confidence: 99%

Neuroprotection by dietary restriction and the PPAR transcription complex

Mobbs

Moreno

Kim

et al. 2012

Translational Neuroscience

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Section: Dmt2: Type 2 Diabetes Mellitus; Mci: Mild Cognitive Impairmentmentioning

confidence: 88%

“…It further facilitates reduction of amyloid plaques, downregulation of Aβ-derived diffusible ligand-binding sites and also to promote tau hypophosphorylation, which stabilizes microtubules. These data and the observation that the combination of insulin and other antidiabetic medication is associated with lower neuritic plaque density [23,34] are providing a rationale for using insulin to treat AD high-risk patients [35][36][37].Insulin resistance, hyperinsulinemia and hyperglycemia can affect the amyloid cascade by reducing Aβ clearance and promote the onset of AD [9,28,38]. Overlapping with AD pathology, they aggravate the progression of neurodegeneration due to oxidative stress, disordered control of protein translation, neurotoxicity by Advanced Glycation End-Products (AGE), mitochondrial dysfunction, neuroinflammation, and a variety of other mechanisms as common pathogenic backgroud culminating in synaptic dysfunction and memory loss [16,26,[39][40][41][42][43][44].…”

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confidence: 94%

The Diabetic Brain and Dementia

Jellinger¹

2015

J Alzheimers Dis Parkinsonism

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Alzheimer's Disease (AD) and Diabetes Mellitus (DM) are the two most common and devastating health problems in the elderly. They share a number of common features among which are important impact on quality of life and substantial health care costs. Epidemiological and biological evidence support a pathophysiological link between Type 2 Diabetes Mellitus (DMT2) and cognitive impairment [1][2][3]. A causative association between DM and Alzheimer's disease has been suggested on the basis of clinical, epidemiological, genetic and experimental studies [2,[4][5][6][7][8][9]. Persons with DM have a higher incidence of cognitive decline and an increased risk of developing AD and other types of dementia, and comorbidity increases the risk [10,11]. Insulin resistance predicts medial temporal hypermetabolism in Mild Cognitive Impairment (MCI) conversion to AD [12] and glucose uptake changes in AD in medial temporal regions predicting worse memory performance [13]. DM has been shown to influence the rate of functional decline among patients with mild AD dementia than in those without comorbid DM [14]. However, the precise mechanisms involved in the development of AD in diabetics are not yet fully understood, and several pathogenic pathways have been discussed [3,4,[15][16][17][18][19][20].Autopsy studies stated that diabetic patients show significantly less AD pathology (senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, etc.) but more cerebrovascular lesions including microvascular lesions and white matter changes than subjects without DM [5,[21][22][23][24][25][26][27]. Vasculo-neural dysfunction has been suggested to represent a potential etiological linkage between DMT2 and AD [6,28], while others suggested that the association between DM and dementia is only partially mediated through cerebrovascular disease and that DM is associated independently with overal dementia among elderly, but not with AD or vascular dementia [29].Positive DMT2 status appears to exacerbate AD pathology in the presence of ApoE ε4 [30]. Although insulin mitigates Aβ deposition and hyperphosphorylation of tau [17,31], DM in combination with ApoE ε4 may lead to excessive phosphorylation of tau [32], but only in subjects with late stage AD [21]. DM modifies metabolism of Aβ and tau causing Aβ/tau-dependent pathological changes, although there is evidence that suggests an interaction of Aβ/tau-dependent and -independent mechanisms [31]. Evidence supports insulin's role in cognition, synaptic remodelling and facilitation of memory [33]. On the other hand, insulin has been shown to modulate the level of Aβ, to protect neurons against detrimental effects of Aβ on synapses [33]. It further facilitates reduction of amyloid plaques, downregulation of Aβ-derived diffusible ligand-binding sites and also to promote tau hypophosphorylation, which stabilizes microtubules. These data and the observation that the combination of insulin and other antidiabetic medication is associated with lower neuritic plaque density [23,34] are providing a...

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“…[8][9][10][11] Among these agents, thiazolidinediones (TZD) exhibited various favorable effects in in vitro and in vivo studies. [10][11][12][13][14] These agents contributed to clearing of amyloid beta protein through apolipoprotein E (ApoE) function. 14) Some reports of clinical trials indicate that TZD improved cognitive function in AD patients.…”

mentioning

confidence: 99%

Apolipoprotein E Gene Polymorphisms Affect the Efficacy of Thiazolidinediones for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Iketani

Ohno

Kawasaki

et al. 2018

Biological & Pharmaceutical Bulletin

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Although several studies have evaluated the efficacy of thiazolidinediones (TZD) for the treatment of Alzheimer's disease (AD), investigation of the impact of apolipoprotein E (ApoE) gene polymorphisms on the efficacy of TZD remains insufficient. We investigated the impact by conducting a systematic review and meta-analysis. MEDLINE, Cochrane Library, and Japana Centra Revuo Medicina were searched to identify relevant studies based on eligibility criteria. Mean differences (MD) of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score with 95% confidence intervals (CI) were calculated for subgroups stratified by ApoE genotype. To evaluate the impact of ApoE gene polymorphisms, meta-regression analysis was also conducted to calculate the regression coefficient (Coef) of ApoE expression status with 95% CI. Three randomized controlled studies comparing rosiglitazone and placebo, with a total of 2381 subjects met the eligibility criteria. Key words Alzheimer's disease; meta-analysis; meta-regression analysis; rosiglitazone; systematic review; thiazolidinedione Dementia affects an estimated 47.5 million individuals worldwide, 60-70% of whom have Alzheimer's disease (AD). 1) Currently, although some drugs such as choline esterase inhibitors and memantine are used for treating AD, their efficacy is limited to delaying disease progression or relieving symptoms. 2) One reason for these limitations may be the fact that AD pathogenesis remains unclear. Therefore, despite the lack of established treatment, drug development has faced difficulties. 3) Several recent studies have reported an association between AD and diabetes mellitus (DM). [4][5][6] These studies demonstrated insulin resistance in the central nervous system (CNS) in some AD patients, which contributed to impaired cognitive functions. This association has been termed type 3 DM. 5,7) Based on this hypothesis, some studies were conducted to investigate the efficacy of anti-diabetic agents for the treatment of AD. 8-11) Among these agents, thiazolidinediones (TZD) exhibited various favorable effects in in vitro and in vivo studies. [10][11][12][13][14] These agents contributed to clearing of amyloid beta protein through apolipoprotein E (ApoE) function. 14) Some reports of clinical trials indicate that TZD improved cognitive function in AD patients. [15][16][17] Additionally, a systematic review and meta-analysis concluded that the efficacy of TZD was significant. 18) Although the efficacy of TZD has been demonstrated, the clinical relevance is limited because the efficacy is lower than that of choline esterase inhibitors.ApoE is a lipoprotein that has genetic polymorphisms (ApoE2, ApoE3, and ApoE4). 19,20) The wild-type ApoE3 constitutes 50-90% of individuals, whereas ApoE4 that constitutes 5-35% of individuals is known to be a genetic risk factor of AD. 19) A clinical trial using intranasal insulin for AD showed improved cognitive function in ApoE4-negative AD patients following short-term intranasal insulin treatment, 8) suggesting tha...

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Rosiglitazone and Pioglitazone for the Treatment of Alzheimer's Disease

Cited by 108 publications

References 25 publications

Neuroprotection by dietary restriction and the PPAR transcription complex

Neuroprotection by dietary restriction and the PPAR transcription complex

The Diabetic Brain and Dementia

Apolipoprotein E Gene Polymorphisms Affect the Efficacy of Thiazolidinediones for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

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