Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that constitutes 60 to 80% of all dementia cases [1
]. It is estimated that 5.3 million Americans are currently suffering from the disease. Without advances in treatment, it is expected that the number of AD patients will double by the year 2050, obviating the need for new and effective therapies.
AD is marked by a decline in cognitive abilities, particularly in the acquisition and retrieval of new memories [2
]. In recent years, epidemiological studies suggest that there is a link between peripheral gluco-regulatory abnormalities and AD [4
]. For example, patients who suffer from severe peripheral insulin resistance and hyperinsulinemia experienced in type 2 diabetes mellitus (T2DM), have an approximately 65% increased risk of developing AD [8
]. Likewise, many AD patients exhibit mild to moderate peripheral insulin resistance, elevated peripheral insulin, and dysregulation of glucose metabolism [9
]. As such, peripheral hyperinsulinemia and gluco-regulatory abnormalities are thought to increase the risk of AD, and patients with AD are more likely to suffer from peripheral gluco-regulatory abnormalities than healthy older adults. Given the converging evidence associating peripheral gluco-regulatory abnormalities and cognitive function in AD, insulin-sensitizing drugs have been proposed as a possible treatment for AD. One such drug is rosiglitazone (RTZ; marketed as Avandia®). RTZ is a member of the class of insulin-sensitizing drugs called thiazolidinediones (TZD). RTZ increases insulin sensitivity by functioning as a ligand to activate the nuclear receptor peroxisome proliferator-activated receptorgamma (PPARγ). PPARγ agonism results in not only increased transcription of insulin responsive genes, PPARγ activation has additional pleiotropic effects on many other signaling pathways; many of which are requisite for neuronal homeostasis and plasticity [10
Indeed, some clinical trials have reported positive results that may presage the future value of PPARγ agonists like RTZ in AD. For example, Dr. Craft’s group has shown cognitive benefit of RTZ in amnestic MCI and mild-to-moderate AD patients lacking the APOE ε4 allele [11
]. Furthermore, this group reported that another TZD pioglitazone, improved cognitive function in AD and MCI patients with mild insulin-resistance more effectively than niteglinide which is a compound that acts as an insulin secretagogue (Watson et al., 2007; Society for Neuroscience Abstract 525.4). These studies suggest that the TDZs may confer a positive benefit for certain subsets of MCI and AD patients. However, the strengths and limitations of TZD treatment are not completely discernible (or apparent) from human studies. It is not clear whether normalizing gluco-regulatory abnormalities, such as peripheral insulin resistance, is alone sufficient enough to improve cognitive performance. Therefore, utilizing an AD mouse model to study the effectiveness of RTZ treatment on cognitive function provides an opportunity to illuminate key variables for optimizing TZD treatment in AD patients.
The transgenic animal line Tg2576 is an extensively characterized mouse model for AD that expresses the 695 splice-variant of the amyloid precursor protein (APP) containing the familial AD ‘Swedish’ mutation KM670/671NL [13
]. Tg2576 mice exhibit a subset of behavioral and pathological features of AD including age-dependent accumulation of beta-amyloid (Aβ) with subsequent learning and memory deficits that worsen in an age-dependent manner [13
]. Our previous work has established that 3 months old (MO) Tg2576 are cognitivxely normal, 5 MO Tg2576 are mildly cognitively-impaired, and 9 MO Tg2576 are severely cognitively-impaired; cognitive function continues to decline as these animals age [14
]. Since these animals do not suffer significant loss of neurons or neurodegeneration, these are not the underlying mechanisms for their age-dependent cognitive decline. A more likely explanation is that cognitive decline in Tg2576 mice is due to age-dependent alterations in the intra- and inter-neuronal signaling mechanisms responsible for synaptic plasticity, learning and memory.
A correlation between metabolism and cognition has been shown in several AD mouse models, and previous work on Tg2576 suggests that signs of peripheral gluco-regulatory abnormalities are apparent by 8 MO [22
]. However, it is not known if earlier existing peripheral gluco-regulatory abnormalities contribute to the onset of cognitive deficits in Tg2576 mice (by 5 months of age) or if reversing peripheral gluco-regulatory abnormalities is sufficient to improve cognitive performance at any age.
In this study, we tested the hypothesis that cognitive improvement following one-month of RTZ treatment correlates with peripheral gluco-regulatory status. Therefore, we conducted a cross-sectional study in which we treated 4, 8, and 12 MO Tg2576 mice (and wild-type (WT) littermates) for one month with RTZ, then tested associative learning and memory performance concomitant with an assessment of peripheral gluco-regulatory status. We found that while 5 MO Tg2576 mice are cognitively-impaired, they do not exhibit any signs of peripheral gluco-regulatory abnormalities, which indicates that peripheral gluco-regulatory status is not a precipitating factor in Tg2576 cognitive impairment. In addition, we discovered that treatment with RTZ in 9 and 13 MO Tg2576 mice effectively normalizes peripheral gluco-regulatory abnormalities, but only reverses cognitive deficits for 9 MO Tg2576 mice. These results suggest that RTZ-mediated cognitive improvement does not correlate with peripheral gluco-regulatory abnormalities per se but likely reflects age-dependent mechanistic differences that underlie cognitive decline in this mouse model. Since RTZ effectiveness at ameliorating cognitive deficits is greater when initiated prior to chronic peripheral gluco-regulatory abnormalities; RTZ’s effectiveness for ameliorating cognitive impairment in Tg2576 AD mice appears to have a limited therapeutic window.