Current Alzheimer Research (v.12, #1)

Meet the Editorial Board: by Frederic Checler (1-1).

The etiopathogenesis of Alzheimer's disease is characterized by beta amyloid Aβ(1-42) toxic fragment aggregation and its association with impaired autophagy. In mitochondria, chronic damage due to transport and enzymatic processes together with the production of reactive oxygen species (ROS) are followed by the subsequent accumulation of Aβ in the form of senile plaques and the accumulation of hyperphosphorylated tau protein in intracellular deposits called tangles. Proteinase-activated receptors (PARs), members of the G protein-coupled receptor (GPCR) family, facilitate and modulate the transcellular transport and distribution of a variety of subcellular molecular components to the lysosomal system and, thus, influence their degradation. A review of the data shows that the activation or inhibition of PARs leads to changes in the process of autophagy, which may influence ROS production and Aβ (1-42) degradation in lysosomes and result in AD pathogenesis.

The β-secretase enzyme BACE1, which initiates the cleavage of amyloid precursor protein (APP) into the amyloid-β (Aβ) peptide, is a prime therapeutic target for Alzheimer's disease (AD). However, recent investigations using genetic animal models raise concern that therapeutic BACE1 inhibition may encounter the dramatic reduction of efficacy in ameliorating AD-like pathology and memory deficits during disease progression. Here, we compared the effects of the potent and selective small-molecule BACE1 inhibitor GRL-8234 in different pathological stages of AD mouse model. Specifically, we administered GRL-8234 (33.4 mg/kg, i.p.) once daily for 2 months to 5XFAD transgenic mice, which showed modest (4 months) and massive (10 months of age) Aβ plaque deposition at starting points. Chronic treatments with GRL-8234 reversed memory impairments, as tested by the spontaneous alternation Y-maze task, in the younger 5XFAD group concomitant with significant reductions in cerebral Aβ42 levels. In contrast, only marginal reductions of Aβ42 were observed in 12-month-old 5XFAD mice treated with GRL-8234 and their memory function remained impaired. We found that not only BACE1 but also full-length APP expression was significantly elevated with progressive Aβ accumulation in 5XFAD mice, while GRL-8234 failed to affect these detrimental mechanisms that further accelerate plaque growth in brains of older 5XFAD mice. Therefore, our results provide important insights into the mechanisms by which Aβ accumulation and related memory impairments become less responsive to rescue by BACE1 inhibition during the course of AD development.

Acute Oral Bryostatin-1 Administration Improves Learning Deficits in the APP/PS1 Transgenic Mouse Model of Alzheimerµs Disease by L.M. Schrott, K. Jackson, P. Yi, F. Dietz, G.S. Johnson, T.F. Basting, G. Purdum, T. Tyler, J.D. Rios, T.P. Castor, J.S. Alexander (22-31).
Background: Previous studies showed that Bryostatin-1, a potent PKC modulator and alphasecretase activator, can improve cognition in models of Alzheimer's disease (AD) with chronic (>10 weeks), intraperitoneal (i.p.) administration of the drug. We compared learning and spatial memory in the APPswe, PSEN1dE985Dbo (APP/PS1) mouse model of AD and studied the ability of acute intraperitoneal and oral Bryostatin-1 to reverse cognitive deficits in this model. Compared to wild-type (WT) mice, APP/PS1 mice showed significant delays in learning the location of a submerged platform in the Morris water maze. Bryostatin-1 was administered over a 2-week course prior to and during water maze testing. Results: Acute i.p. Bryostatin-1 administration did not improve latency to escape but oral Bryostatin-1 significantly improved memory (measured by a reduction in latency to escape). This benefit of oral Bryostatin-1 administration was most apparent during the first 3 days of testing. These findings show that: 1) Bryostatin-1 is orally active in models of learning and memory, 2) this effect can be produced in less than 2 weeks and 3) this effect is not seen with i.p. administration. We conclude that oral Bryostatin-1 represents a novel, potent and long-acting memory enhancer with future clinical applications in the treatment of human AD.

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimerµs Disease by Robert J. Baranello, Krishna L. Bharani, Vasudevaraju Padmaraju, Nipun Chopra, Debomoy K. Lahiri, Nigel H. Greig, Miguel A. Pappolla, Kumar Sambamurti (32-46).
Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

No Significant Effect of 7,8-Dihydroxyflavone on APP Processing and Alzheimer-Associated Phenotypes by Weitao Zhou, Xiaoyong Li, Daochao Huang, Weihui Zhou, Tingyu Li, Weihong Song (47-52).
It is reported that 7,8-dihydroxyflavone (DHF), a TrkB agonist, has beneficial effects on neuronal excitotoxicity, stroke, and Parkinson disease in animal models by enhancing axon regeneration, muscle reinnervation and neuromuscular transmission. The effect of DHF on AD neuropathology remains not well defined. In this study we examined whether DHF affects APP processing and cognitive functions in vitro and in vivo. We found that DHF had no significant effect on amyloid β precursor protein (APP), BACE1 and amyloid β protein (Aβ). DHF had little effect on APP processing in cell cultures. DHF treatment did not reduce the deposition of Aβ to form neuritic plaques in the brain of AD model mice APP23/PS45. Furthermore, DHF did not alleviate learning and memory impairments in the AD model mice. Our study suggest that further extensive and careful studies are warranted for considering DHF as a new therapeutic agent for reducing amyloid pathology and alleviating cognitive deficits for AD treatment.

Background: ACTION, a 24-week, prospective, randomized, parallel-group, double-blind study in patients with severe Alzheimer's disease (AD), demonstrated significant efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on the Severe Impairment Battery (SIB) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Overall, 61% of the study population received at least 1 dose of concomitant memantine, regardless of dose or duration. This retrospective analysis investigated the effects of concomitant memantine on the efficacy, safety and tolerability of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch. Methods: Patients were stratified according to whether or not they received at least one dose of concomitant memantine during the double-blind phase. Changes from baseline on the SIB and ADCS-ADL-SIV were compared using analysis of covariance (ANCOVA) with treatment, pooled center, memantine usage and treatment-by-memantine as factors, and baseline as a covariate. Safety and tolerability were assessed. Results: Memantine-treated patients were younger than those not receiving memantine (mean 75.9 and 78.8 years, respectively), with a lower screening Mini-Mental State Examination (8.6 and 9.2, respectively). ANCOVA confirmed there was no significant interaction (p>0.1) between study treatment and memantine use on the SIB or ADCS-ADL-SIV. The incidence of adverse events was: 71.4%, 13.3 mg/24 h patch with memantine; 79.7%, 13.3 mg/24 h patch alone; 74.7%, 4.6 mg/24 h patch with memantine; and 71.1%, 4.6 mg/24 h patch alone. Conclusion: These data suggest benefit of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch, regardless of concomitant memantine use. The incidence of adverse events with highdose patch was similar in memantine-treated patients and those not receiving memantine.

Expanded Temporal Binding Windows in People with Mild Cognitive Impairment by Jason S. Chan, Jochen Kaiser, Mareike Brandl, Silke Matura, David Prvulovic, Michael J. Hogan, Marcus J. Naumer (61-68).
Previous studies investigating mild cognitive impairment (MCI) have focused primarily on cognitive, memory, attention, and executive function deficits. There has been relatively little research on the perceptual deficits people with MCI may exhibit. This is surprising given that it has been suggested that sensory and cognitive functions share a common cortical framework [1]. In the following study, we presented the sound-induced flash illusion (SiFi) to a group of participants with mild cognitive impairment (MCI) and healthy controls (HC). The SiFi is an audio-visual illusion whereby two-beeps and one-flash are presented. Participants tend to perceive two flashes when the time-interval between the auditory beeps is small [2, 3]. Participants with MCI perceived significantly more illusions compared to HC over longer auditory time-intervals. This suggests that MCIs integrate more (arguably irrelevant) audiovisual information compared to HCs. By incorporating perceptual tasks into a clinical diagnosis it may be possible to gain a more comprehensive understanding into the disease, as well as provide a more accurate diagnose to those who may have a language impairment.

Predicting Progression from Cognitive Impairment to Alzheimerµs Disease with the Disease State Index by Anette Hall, Jussi Mattila, Juha Koikkalainen, Jyrki Lotjonen, Robin Wolz, Philip Scheltens, Giovanni Frisoni, Magdalini Tsolaki, Flavio Nobili, Yvonne Freund-Levi, Lennart Minthon, Lutz Frolich, Harald Hampel, Pieter Jelle Visser, Hilkka Soininen (69-79).
We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DESCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out crossvalidation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, theywere 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression.

Purpose: To examine hippocampal differences between Alzheimer disease (AD), amnestic mild cognitive impairment (aMCI) and normal aging. Materials and methods: This study was approved by the local ethics review board, and informed consent was obtained from volunteers/guardians. The study comprised 60 subjects: 20 aMCI patients, 20 AD patients and 20 normal controls (NC group). Magnetic resonance imaging and diffusion kurtosis imaging of the hippocampus were performed. Nonlinear fitting routines and equations were used to calculate mean diffusion (MD) and mean kurtosis (MK). Analysis of variance was used to compare the bilateral MK/MD values/volumes of the hippocampus for the three groups using the Fisher least significant difference test (a two-sample t-test comparison). Pearson correlation coefficients were calculated for the correlations between mini-mental state examination (MMSE) scores and MK/MD values/volumes. Results: There were significant differences between the AD and NC groups and between the AD and aMCI groups in terms of normalized bilateral hippocampal volume. There were significant differences between the NC, aMCI and AD groups in terms of both right and left hippocampus MK values. For the right hippocampus MD values, there was a significant difference between the NC and AD groups. For the left hippocampus MD values, there were significant differences between the AD and NC groups and between the AD and aMCI groups. Pearson correlation coefficients for all correlations between MMSE scores and hippocampus MK/MD values/volumes were significant. Conclusion: The bilateral hippocampal MK/MD values may be more sensitive than volumes in the diagnosis of aMCI and AD patients.

Associations between Alzheimerµs Disease and Blood Homocysteine, Vitamin B12, and Folate: A Case-Control Study by Hui Chen, Shuai Liu, Lu Ji, Tianfeng Wu, Fei Ma, Yong Ji, Yuying Zhou, Miaoyan Zheng, Meilin Zhang, Guowei Huang (88-94).
Background: There is a growing focus on nutritional therapy for Alzheimer's disease (AD), and controversy exists regarding the association between AD and homocysteine (Hcy), vitamin B12, and folate levels. Objective: The present study evaluated the association between AD and the combined levels of Hcy, vitamin B12, and folate. Methods: This case-control study consisted of 115 patients with AD and 115 matched controls. Serum folate and vitamin B12 were measured using an automated immunoassay analyzer. Plasma Hcy was measured using high-performance liquid chromatography. The association between AD and Hcy, vitamin B12, and folate was analyzed using binary logistic regression, adjusted for age and sex. Results: With the combination of normal blood Hcy, vitamin B12, and folate levels as the reference category, low vitamin B12 in subjects with normal Hcy and folate was associated with AD (adjusted odds ratio [OR], 4.6; 95% confidence interval [CI]: 1.6-13.2). The combination of low vitamin B12 and folate in subjects with normal Hcy was associated with AD (adjusted OR, 4.3; 95% CI: 1.3-14.6). The combination of high Hcy and low folate levels in patients with normal vitamin B12 was associated with AD (adjusted OR, 17.0; 95% CI: 5.4- 53.4). The combination of high Hcy, low vitamin B12, and any folate level was associated with AD (adjusted OR, 30.5; 95% CI: 9.7-95.9). Conclusion: Vitamin B12 was directly associated with AD. The combination of high Hcy, low vitamin B12, and any folate level represented the poorest association with AD.