Alzheimer Disease: Gray AJ

Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE, Aisen PS, Matsuoka Y. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. · Brain Res. · Pubmed #18486110 No free full text.

Abstract: Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.

Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li HF, Feng L, Lecanu L, Walker BR, Planel E, Arancio O, Gozes I, Aisen PS. · Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Road N.W., Washington, DC 20057, USA. · J Pharmacol Exp Ther. · Pubmed #18199809 links to  free full text

Abstract: Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.

Takata K, Hirata-Fukae C, Becker AG, Chishiro S, Gray AJ, Nishitomi K, Franz AH, Sakaguchi G, Kato A, Mattson MP, Laferla FM, Aisen PS, Kitamura Y, Matsuoka Y. · Department of Neurobiology, Kyoto Pharmaceutical University and 21st Century COE Program, Kyoto 607-8414, Japan. · Eur J Neurosci. · Pubmed #17970733 No free full text.

Abstract: Accumulation of amyloid beta (Abeta) is a pathological hallmark of Alzheimer's disease, and lowering Abeta is a promising therapeutic approach. Intact anti-Abeta antibodies reduce brain Abeta through two pathways: enhanced microglial phagocytosis and Abeta transfer from the brain to the periphery (Abeta sequestration). While activation of microglia, which is essential for microglial phagocytosis, is necessarily accompanied by undesired neuroinflammatory events, the capacity for sequestration does not seem to be linked to such effects. We and other groups have found that simple Abeta binding agents are sufficient to reduce brain Abeta through the sequestration pathway. In this study, we aimed to eliminate potentially deleterious immune activation from antibodies without affecting the ability to induce sequestration. The glycan portion of immunoglobulin is critically involved in interactions with immune effectors including the Fc receptor and complement c1q; deglycosylation eliminates these interactions, while antigen (Abeta)-binding affinity is maintained. In this study, we investigated whether deglycosylated anti-Abeta antibodies reduce microglial phagocytosis and neuroinflammation without altering the capacity to induce Abeta sequestration. Deglycosylated antibodies maintained Abeta binding affinity. Deglycosylated antibodies did not enhance Abeta phagocytosis or cytokine release in primary cultured microglia, whereas intact antibodies did so significantly. Intravenous injection of deglycosylated antibodies elevated plasma Abeta levels and induced Abeta sequestration to a similar or greater degree compared with intact antibodies in an Alzheimer's transgenic mouse model without or with Abeta plaque pathology. We conclude that deglycosylated antibodies effectively induced Abeta sequestration without provoking neuroinflammation; thus, these deglycosylated antibodies may be optimal for sequestration therapy for Alzheimer's disease.

Matsuoka Y, Gray AJ, Hirata-Fukae C, Minami SS, Waterhouse EG, Mattson MP, LaFerla FM, Gozes I, Aisen PS. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. · J Mol Neurosci. · Pubmed #17478890 No free full text.

Abstract: Accumulation of beta-amyloid (Abeta) peptide and hyperphosphorylation of tau in the brain are pathological hallmarks of Alzheimer's disease (AD). Agents altering these pathological events might modify clinical disease progression. NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) is an octapeptide that has shown neuroprotective effects in various in vitro and in vivo neurodegenerative models. Previous studies showed that NAP protected against Abeta-induced neurotoxicity, inhibited Abeta aggregation, and, by binding to tubulin, prevented disruption of microtubules. In this study, we investigated the effect of NAP on Abeta and tau pathology using a transgenic mouse model that recapitulates both aspects of AD. We administered NAP intranasally (0.5 microg/mouse per day, daily from Monday through Friday) for 3 mo, starting from 9 mo of age, which is a prepathological stage in these mice. NAP treatment significantly lowered levels of Abeta 1-40 and 1-42 in brain. In addition, NAP significantly reduced levels of hyperphosphorylated tau. Of particular interest, hyperphosphorylation at the threonine 231 site was reduced; phosphorylation at this site influences microtubule binding. Our results indicate that NAP treatment of transgenic mice initiated at an early stage reduced both Abeta and tau pathology, suggesting that NAP might be a potential therapeutic agent for AD.

Nelson RL, Guo Z, Halagappa VM, Pearson M, Gray AJ, Matsuoka Y, Brown M, Martin B, Iyun T, Maudsley S, Clark RF, Mattson MP. · Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA. · Exp Neurol. · Pubmed #17368447 links to  free full text

Abstract: A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Abeta) and numbers of Abeta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans.

Gray AJ, Sakaguchi G, Shiratori C, Becker AG, LaFrancois J, Aisen PS, Duff K, Matsuoka Y. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. · Neuroreport. · Pubmed #17314674 No free full text.

Abstract: Accumulation of amyloid beta in the brain is a pathological hallmark of Alzheimer's disease, and the reduction of amyloid beta has been proposed as a primary therapeutic target. Mice immunized against amyloid beta and mice infused with anti-amyloid beta antibody (active and passive immunization, respectively) have reduced brain amyloid beta levels, and two mechanisms have been proposed: microglial phagocytosis in the brain and enhancement of amyloid beta efflux by antibodies present in the periphery (sequestration). The optimal antibody for microglial phagocytosis has been shown to be N-terminal-specific antibody; however, the potency of C-terminal-specific antibody in sequestration remains unclear. In this study, we found that anti-amyloid beta 40-specific antibody induces amyloid beta sequestration. These results indicate that C-terminal antibodies may be useful in amyloid beta sequestration therapy.

Horikoshi Y, Sakaguchi G, Becker AG, Gray AJ, Duff K, Aisen PS, Yamaguchi H, Maeda M, Kinoshita N, Matsuoka Y. · Immuno-Biological Laboratories Co., Ltd., Fujioka-shi, Gunma 375-0005, Japan. · Biochem Biophys Res Commun. · Pubmed #15184044 No free full text.

Abstract: Alzheimer's disease (AD) is a neurodegenerative affliction associated with memory dysfunction. Senile plaques are a pathological hallmark of AD, and amyloid beta (Abeta) peptides are a major component of these plaques. Abeta peptides are derived from proteolytic cleavage of the Abeta protein precursor (APP) by beta- and gamma-secretases to generate two principal species, Abeta1-40 and Abeta1-42. We have developed antibodies against the N- and C-termini of these peptides, and an ELISA for accurate and sensitive quantitative assessment. Sandwich ELISA composed of N-terminus (Abeta1) end-specific antibody, clone 82E1, and C-termini end-specific antibodies, and clones 1A10 and 1C3 for Abeta40 and Abeta42, respectively, detects full-length Abeta1-40 and 1-42 with a sensitivity in the sub single digit fmol/ml (equivalent to single digit pg/ml) range with no cross-reactivity to APP. A combination of C-termini antibodies and an antibody against the middle region of Abeta detects mouse Abeta in non-transgenic mouse brains.

Gray AJ, Staples V, Murren K, Dhariwal A, Bentham P. · Worcestershire Community Healthcare NHS Trust, UK. · Int J Geriatr Psychiatry. · Pubmed #11376468 No free full text.

Abstract: AIMS: It is now well established that there are abnormalities in the sense of smell in patients suffering from Alzheimer's disease (AD). They have both raised olfactory thresholds and impaired odour identification. The situation in vascular dementia is unclear. We used the University of Pennsylvania Smell Identification Test (UPSIT), a 40-item, forced choice, cued, 'scratch-and- sniff' test, to examine olfactory identification in vascular dementia and to determine whether it would differentiate the disorder from AD and normal elderly. METHODS: We investigated three matched subject groups: 13 people having a Cambridge Examination for Mental Disorders in the Elderly (CAMDEX) diagnosis of definite senile dementia of Alzheimer type, 13 having a CAMDEX diagnosis of definite vascular dementia and 13 non-cognitively impaired controls. The subjects were then tested with the UPSIT in their own home by an independent blind researcher to see if the test could distinguish the different diagnostic groups in this setting. RESULTS: The median UPSIT score was 30 (out of a maximum of 40) for controls, 12 for the vascular group and 15 for the AD group. The difference was significant (p = 0.05) between both demented groups and the normal controls. Similarly there was a significant difference in the UPSIT score between the AD group and controls (p = 0.001) and between the vascular dementia group and controls (p = 0.001), but there was no significant difference between the AD group and the vascular dementia group. The UPSIT score correlated strongly with the degree of cognitive impairment as measured by the CAMCOG (r(s) = 0.683, p = 0.01) CONCLUSIONS: Patients with vascular dementia had a similar degree of olfactory impairment to those with AD. The UPSIT successfully differentiated between dementia patients and normal elderly British subjects tested in their own homes. The UPSIT did not differentiate between those with AD and vascular dementia.