Irit Lubitz

Dietary advanced glycation end products are associated with decline in memory in young elderly.

We recently reported that serum methylglyoxal (sMG) is associated with a faster rate of decline in a global measure of cognition in the very elderly. We here provide for the first time evidence in which high levels of dietary AGE (dAGE) are associated with faster rate of decline in memory in 49 initially non-demented young elderly (p=0.012 in mixed regression models adjusting for sociodemographic and cardiovascular factors). Since modifying the levels of AGEs in the diet may be relatively easy, these preliminary results suggest a simple strategy to diminish cognitive compromise in the elderly and warrant further investigation.

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimers disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42, AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD‐like model mice on high‐AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood–brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle‐linked disease epidemic.

Combined local blood-brain barrier opening and systemic methotrexate for the treatment of brain tumors.

Despite aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme patients, in part due to poor penetration of most drugs across the blood–brain barrier (BBB). We propose a minimal-invasive combined treatment approach consisting of local BBB disruption in the tumor in parallel to systemic drug administration. Local BBB disruption is obtained by convection-enhanced delivery of a novel BBB disruption agent, enabling efficient/targeted delivery of the systemically administered drug by the tumors own vasculature. Various human serum albumin (HSA) analogs were synthesized and screened for BBB disruption efficacy in custom in vitro systems. The candidate analogs were then delivered into naïve rat brains by convection-enhanced delivery and screened for maximal BBB disruption and minimal brain toxicity. These studies found a noncationized/neutralized analog, ethylamine (EA)–HSA, to be the optimal BBB-opening agent. Immunocytochemical studies suggested that BBB disruption by EA–HSA may be explained by alterations in occludin expression. Finally, an efficacy study in rats bearing intracranial gliomas was performed. The rats were treated by convection-enhanced delivery of EA–HSA in parallel to systemic administration of Methotrexate, showing significant antineoplastic effects of the combined approached reflected in suppressed tumor growth and significantly (~x3) prolonged survival.

Non-viability of crossing the Alzheimer mouse model Tg2576 with the type 2 diabetes mouse model ob/ob

Numerous epidemiologic studies suggest that type 2 diabetes (T2D) is associated with an increased risk for Alzheimer’s disease (AD). Therefore, the search for potential cause and effect relationships and underlying mechanisms has become intensive. Development of a valid animal model expressing both diseases may facilitate disentangling such mechanisms thus, expediting translation to prevention and treatment of dementia in the ever-growing elderly population.We thus attempted to generate an animalmodel by crossbreeding Tg2576 mice, an AD-type model (Hsiao et al., 1996)dwhich expresses the human 695-aa isoform of amyloid precursor protein (APP) containing the Swedish double mutation (APPswe) driven by a hamster prion promoterdwith the leptindeficient T2D mouse model, ob/ob. We chose the Tg2576 model because these mice are well characterized in the literature, their pathology develops relatively slowly, but rapidly enough, and thus the model is more pertinent to future human applications, and they have relatively high survival (by 12 months about 85% survive) (King and Arendash, 2002). The ob/ob mouse model, T2D model develops insulin resistance, hyperglycemia, obesity, and complications of diabetes such as neuropathy (Hudkins et al., 2010). This T2D model has also been studied in the context of aging (Ren et al., 2010; Sjoholmet al., 2001) and has the same genetic background (C57BL/6J) as the Tg2576 making it particularly convenient for crossing. The Tg2576-ob/ob mice were produced by crossbreeding the 2 mouse types. Male hemizygous Tg2576 mice were crossbred with female heterozygous ob/þ mice to generate Tg2576-ob/þ and ob/þ founder mice. We then intercrossed these mice to obtain Tg2576-ob/ ob. The Tg2576-ob/ob as well as their littermates were transferred to B6 inbred background and were used in this study. Genotyping was performed at 6 weeks. From 471 mice that were born in this process, we obtained 30 Tg2576-ob/obmice,16males and 14 females, making the probability of having Tg2576-ob/ob crossbred mice 6.3%, about half the expected 12.5%, suggesting they die at a very early stage, possibly preand postgestationally. The Tg2576-ob/ob mice showed early-onset obesity compared with Tg2576, so as expected, the general appearance and body weight were similar to those of the ob/ob mice. As early as at 8 weeks, Tg2576-ob/ob mice showed severe hyperglycemia (Fig. 1) averaging twice as much as the ob/ob mice and almost 3-fold the glucose levels of Tg2576 and wild-type (WT) mice, which were similar (F 1⁄4 14.144; df [3, 23] p < 0.0001). Tg2576-ob/ob had significantly higher total cholesterol (F 1⁄4 15.587; df [3, 14]; p < 0.0001) and nominally elevated triglycerides (F 1⁄4 0.953; df [3, 14]; p 1⁄4 0.44) (Fig. 2) compared with Tg2576 and WT mice. We report

Potential contribution of the Alzheimer's disease risk locus BIN1 to episodic memory performance in cognitively normal Type 2 diabetes elderly.

In recent years, several promising susceptibility loci for late-onset Alzheimers disease (AD) were discovered, by implementing genome-wide association studies (GWAS) approach. Recent GWAS meta-analysis has demonstrated the association of 19 loci (in addition to the APOE locus) with AD in the European ancestry population at genome-wide significance level. Since Type 2 Diabetes (T2D) is a substantial risk factor for cognitive decline and dementia, the 19 single nucleotide polymorphisms (SNPs) that represent the 19 AD loci were studied for association with performance in episodic memory, a primary cognitive domain affected by AD, in a sample of 848 cognitively normal elderly Israeli Jewish T2D patients. We found a suggestive association of SNP rs6733839, located near the bridging integrator 1 (BIN1) gene, with this phenotype. Controlling for demographic (age, sex, education, disease duration and ancestry) covariates, carriers of two copies of the AD risk allele T (TT genotype) performed significantly worse (p=0.00576; p=0.00127 among Ashkenazi origin sub-sample) in episodic memory compared to carriers of the C allele (CT+CC genotypes). When including additional potential covariates (clinical and APOE genotype), results remained significant (p=0.00769; p=0.00148 among Ashkenazi). Interestingly, as validated in multiple large studies, BIN1 is one of the most established AD risk loci, with a high odds ratio. Although preliminary and require further replications, our findings support a contribution of BIN1 to individual differences in episodic memory performance among T2D patients.

COMBINATION THERAPY OF TYPE 2 DIABETES MEDICATIONS AS A TREATMENT TARGET FOR ALZHEIMER DISEASE

P2-107 COMBINATION THERAPY OF TYPE 2 DIABETES MEDICATIONS AS A TREATMENT TARGET FOR ALZHEIMER DISEASE Dana Atrakchi-Baranes, Irit Lubitz, Shemesh Chen, Pavel Katsel, Sigal Liraz-Zaltsman, Tali Licht, Inbal Sharvit-Ginon, Shirin Elhaik Goldman, Itzik Cooper, Vahram Haroutunian, Michal Schnaider Beeri, The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat Gan, Israel; Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn School of Medicine at Mount Sinai, Manhattan, NY, USA. Contact e-mail: dana.atrakchi@gmail.com

The Alzheimer's disease risk loci bin1 is associated with poorer episodic memory performance in cognitively normal type 2 diabetes elderly

tissue. Antibodies against tau, amyloid b, a-synuclein and TDP-43 were used. Results:At age 59, the proband, a female, presented motor dysfunction while dancing. Neurological and neuropsychological evaluation revealed a mild cognitive impairment, at age 63. She was diagnosed with Parkinsonism at age 65; she declined rapidly and at 66 became aphasic. At this time, a neurologic exam revealed progressive dysfluency and poor left arm dexterity. Later, resting right hand tremor and short-stepped gait were noted. Neurological examination, at age 68, showed minimal verbal output; comprehension, reading and writing were impaired. Rigidity, bradykinesia and impaired postural reflexes were recorded. MRI showed atrophy of frontal and temporal lobes. She became dependent on activities of daily living and died at age 68. Blood serum revealed decreased levels of progranulin. At autopsy, the fresh brain weighed 900 grams, showing severe atrophy of frontal and temporal lobes. Histologically, there was severe neuronal loss and gliosis in neocortex, caudate nucleus, putamen, globus pallidus, hippocampus, dentate nucleus, inferior olivary nucleus. Atrophy of the centrum semiovale was observed. TDP-43-immunoreactive neuronal cytoplasmic and, occasionally, intranuclear inclusions as well as dystrophic neurites were detected in frontal, parietal and temporal cortices, cingulate gyrus, precuneus, thalamus, subthalamic nucleus, hippocampus, and entorhinal cortex. Rare neurofibrillary tangles and tau-immunoreactive neurons were found in putamen, substantia innominata, hippocampus, and entorhinal cortex. Analysis of DNA extracted from blood revealed a g.1642delTGAG deletion in a putative splicing consensus sequence in GRN. The study of this family (8 siblings) demonstrated segregation of the variant with disease. Conclusions:The study of this patient and future studies of other family members will give insight about the natural history of disease, including biomarker and brain imaging alterations in asymptomatic and symptomatic subjects.