Recent genome wide association studies (GWAS) have implicated bridging integrator 1 (BIN1) as a late-onset Alzheimer’s disease (AD) susceptibility gene. There are at least 15 different known isoforms of BIN1, with many being expressed in the brain including the longest isoform (iso1), which is brain-specific and localizes to axon initial segments and nodes of Ranvier. It is currently unknown what role BIN1 plays in AD. We analyzed BIN1 protein expression from a large number (N = 71) of AD cases and controls from five different brain regions [hippocampus, inferior parietal (IP) cortex, inferior temporal (IT) cortex, frontal cortex (BA9), and superior and middle temporal gyri (SMTG)]. We found that the amount of the largest isoform of BIN1 was significantly reduced in the AD brain compared to age-matched controls, and smaller BIN1 isoforms were significantly increased. Further, BIN1 was significantly correlated with the amount of neurofibrillary tangle (NFT) pathology but not with either diffuse or neuritic plaques, or with the amount of amyloid-β peptide. BIN1 is known to be abnormally expressed in another human disease, myotonic dystrophy, which also features prominent NFT pathology. These data suggest that BIN1 is likely involved in AD as a modulator of NFT pathology, and that this role may extend to other human diseases that feature tau pathology.

Glycogen synthase kinase (GSK) -3β is a multifunctional protein that has been implicated in the pathological characteristics of Alzheimer’s disease (AD), including the heightened levels of neurofibrillary tangles, amyloid-beta (Aβ) and neurodegeneration. In this study we used 12 month old SAMP8 mice, an AD model, to examine the effects GSK-3β may cause regarding the cognitive impairment and oxidative stress associated with AD. To suppress the level of GSK-3β, SAMP8 mice were treated with an antisense oligonucleotide (GAO) directed at this kinase. We measured a decreased level of GSK-3β in the cortex of the mice, indicating the success of the antisense treatment. Learning and memory assessments of the SAMP8 mice were tested post-antisense treatment using an aversive T-maze and object recognition test, both of which observably improved. In cortex samples of the SAMP8 mice, decreased levels of protein carbonyl and protein-bound HNE were measured indicating decreased oxidative stress. Nuclear factor erythroid -2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. Lastly, we examined the ability of GAO to cross the blood-brain barrier and determined it to be possible. The results presented in this study demonstrate that reducing GSK-3 with a phosphorothionated antisense against GSK-3 improves learning and memory, reduces oxidative stress, possibly coincident with increased levels of the antioxidant transcriptional activity of Nrf2, and decreases tau phosphorylation. Our study supports the notion of GAO as a possible treatment for AD.

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer’s disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPΔNL/ΔNLx PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aβ deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aβ was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aβ-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPΔNLx PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aβ deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics.

Obesity and type 2 diabetes mellitus (T2DM) convey an increased risk for developing dementia. The microtubule associated protein tau is implicated in neurodegenerative disease by undergoing hyperphosphorylation and aggregation, leading to cytotoxicity and neurodegeneration. Enzymes involved in the regulation of tau phosphorylation, such as GSK3β, are tightly associated with pathways found to be dysregulated in T2DM. We have shown previously that leptin resistant mice, which develop obesity and a diabetic phenotype, display elevated levels of tau phosphorylation. Here we show cells cultured with leptin, an adipokine shown to have neuroprotective effects, reduces tau phosphorylation. To explore how this mechanism works in vivo we transduced an existing diabetic mouse line (Leprdb/db) with a tau mutant (tauP301L) via adeno-associated virus. The resulting phenotype included a striking increase in tau phosphorylation and the number of neurofibrillary tangles found within the hippocampus. We conclude that leptin resistance-induced obesity and diabetes accelerates the development of tau pathology. This model of metabolic dysfunction and tauopathy provides a new system in which to explore the mechanisms underlying the ways in which leptin resistance and diabetes influence development of tau pathology, and may ultimately be related to the development of neurofibrillary tangles.

Alzheimer’s Disease (AD) is the most common age-related neurodegenerative disease, affecting an estimated 5.3 million people in the United States. While many factors likely contribute to AD progression, it is widely accepted that AD is driven by the accumulation of β-amyloid (Aβ), a small, fibrillogenic peptide generated by the sequential proteolysis of the amyloid precursor protein by the β- and γ-secretases. Though the underlying causes of Aβ accumulation in sporadic AD are myriad, it is clear that lifestyle and overall health play a significant role. The adipocyte-derived hormone leptin has varied systemic affects, including neuropeptide release and neuroprotection. A recent study by Lieb et al (2009) showed that individuals with low plasma leptin levels are at greater risk of developing AD, through unknown mechanisms. In this report, we show that plasma leptin is a strong negative predictor of Aβ levels in the mouse brain, supporting a protective role for the hormone in AD onset. We also show that the inhibition of Aβ accumulation is due to the downregulation of transcription of the γ-secretase components. On the other hand, β-secretase expression is either unchanged (BACE1) or increased (BACE2). Finally, we show that only presenilin 1 (PS1) is negatively correlated with plasma leptin at the protein level (p<0.0001). These data are intriguing and may highlight a role for leptin in regulating the onset of amyloid pathology and AD.