Current Alzheimer Research (v.13, #8)

Meet Our Associate Editor by Gad A. Marshall (845-845).

Lithium is associated with various effects on immune functions, some of which are still poorly understood. The roles of many cytokines have been characterized in a variety of neurodevelopmental processes including neurogenesis, neuronal and glial cell migration, proliferation, differentiation, synaptic maturation and synaptic pruning. This work aims to evaluate the effects of different doses of lithium (0.02; 0.2 and 2mM) on the secretion of cytokines in co-cultures of cortical and hippocampal neurons with glial cells. Our results indicate that chronic treatment with lithium chloride at subtherapeutic concentrations are able to modify the secretion of pro- and anti-inflammatory interleukins in co-cultures of cortical and hippocampal neurons with glial cells.

The Putative Use of Lithium in Alzheimer's Disease by Gerwyn Morris, Michael Berk (853-861).
Alzheimer's disease is a progressive neurodegenerative illness characterized by the invariant existence of ?-amyloid plaques and neurofibrillary tangles. Presently approved pharmaceutical approaches offer only marginal efficacy and as yet there is no effective treatment which reverses or arrests the disease. Thus far, drugs targeting any single aspect of disease pathology have proved to be a failure or at best provided very slight clinical benefit. The consistent failure of drugs targeting aspects of the A? cascade has questioned the causal role of this pathway. There is a growing appreciation that the pathogenesis of the illness is multifactorial with Amyloid Beta, Phosphorylated Tau (ptau), inflammation, mitochondrial dysfunction, calcium dyshomeostasis, heavy metal imbalances, and GSK-3 interact in a highly complex manner to provoke a selfsustaining spiraling cascade of pathology, driving disease progression. In the light of such complex pathology, the failure of drugs aimed a targeting single molecules is not surprising as such approaches are usually ineffective against other complex diseases with a multifactorial pathogenesis. Combination therapies or multi target drugs might be more effective in controlling such illnesses. The putative neuroprotective effects of Lithium are achieved via the positive modulation of numerous homeostatic mechanisms regulating autophagy, oxidative stress, inflammation, and mitochondrial dysfunction likely achieved by inhibiting GSK-3 and inositol-145 triphosphate. Data regarding efficacy in human trials and animal models of AD are mixed, but recent data using “microdose” lithium in mild cognitive impairment is encouraging, hence lithium could be a putative multi target treatment in these patients. However, additional well designed long-term trials are needed to confirm its efficacy and safety, given that long term use is necessary to achieve reasonable therapeutic benefit.

Neuroprotective Effects of Lithium in Human Brain? Food for Thought by Tomas Hajek, Michael W. Weiner (862-872).
Background: There is a growing body of pre-clinical evidence suggesting that lithium (Li) may protect neurons from a range of neurotoxic insults, hence the term neuroprotective effects. Does Li have similar effects also in human subjects? Methods: We reviewed the neuroimaging literature investigating the association between Li treatment and brain structure. Results: There is level I evidence for positive association between Li treatment and brain grey matter volume, which is one of the most replicated neuroimaging findings. It has been reported in the majority of cross sectional studies, all 8 prospective studies, including a randomized controlled trial as well as in 2 meta-analyses and one mega-analysis. The association between Li treatment and grey matter volume occurs regardless of mood state, diagnostic subtype, presence or absence of concomitant medications. It was documented in multiple brain regions, including hippocampus, amygdala, anterior cingulate, subgenual cingulate, inferior frontal gyrus, postcentral gyrus, habenula. Conclusion: Although some methodological and clinical issues complicate the interpretation of findings, there is robust and highly replicated level 1 evidence for positive association between Li treatment and grey matter volumes. These "neuroprotective" effects of Li have been shown even in healthy subjects and appear independent of prophylactic treatment response. Consequently, Li might help maintain brain health even in patients without bipolar disorders and could possibly demonstrate diseasemodifying properties in neurodegenerative disorders.

Background: Lithium shows neuroprotective and neurotrophic effects in vitro and in vivo. Due to its involvement in hippocampal neurogenesis and the interaction with beta-amyloid and neurofibrillary tangle metabolism it has been hypothesized that lithium could have the potential to influence the development of dementia. Method: Using the PubMed database and cross-reference search strategies our aim was to specifically identify population (cohort or case-control) studies investigating the association between lithium and dementia. Results: Data from large cohort studies suggest an association between lithium treatment and dementia risk reduction or reduced dementia severity. Studies with smaller sample sizes yield more variable findings. Conclusions: Lithium may reduce the risk of dementia among middle-aged and older people. Beneficial lithium effects are possibly limited to specific types of neurodegenerative processes.

Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders by Orestes V. Forlenza, Ivan Aprahamian, Vanessa J. de Paula, Tomas Hajek (879-886).
Background: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer's disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects. Methods: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014. Results: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease. Conclusion: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.

Effect of Lithium on Neurocognitive Functioning by Janusz K. Rybakowski (887-893).
Lithium is the first choice drug for the long-term prophylaxis of depressive and manic episodes in bipolar disorder (BD). Both experimental and clinical studies show either neuroprotective or neurotoxic effects of lithium on brain function, reflecting the propensity of lithium to affect different brain structures. In most experimental studies, lithium, in therapeutic doses, exerts a favourable influence on various cognitive functions. Patients with BD present cognitive problems of mild intensity across mood states, worsening during manic or depressive episodes and, sometimes, also persisting during euthymia. Meta-analyses, comparing bipolar patients treated with lithium with those without the drug show a moderate negative effect of this drug on cognition and, among clinicians, negative impact on cognitive functioning is considered one of the side effect of the drug. In some studies, the effect of lithium on cognitive function in BD was shown to be associated with a prophylactic efficacy of the drug against an occurrence of affective episodes. Excellent lithium responders, having no affective recurrences during lithium therapy, perform on cognitive functions tests similar to those of age-matched, healthy control subjects. Some studies also found a reduction by lithium the risk of dementia in BD subjects. Possible mechanisms alleviating negative impact of lithium on cognition in BD can be connected with the prevention of affective recurrences, improvement of neural plasticity, antiviral action against herpes infection and using the drug in appropriate doses.

Glial Cells - The Key Elements of Alzheimers Disease by David Dzamba, Lenka Harantova, Olena Butenko, Miroslava Anderova (894-911).
Alzheimer's disease (AD) is a complex neurodegenerative disorder with major clinical hallmarks of memory loss, dementia, and cognitive impairment. Besides the extensive neuron-oriented research, an increasing body of evidence suggests that glial cells, namely astrocytes, microglia, NG2 glia and oligodendrocytes, may play an important role in the pathogenesis of this disease. In the first part of this review, AD pathophysiology in humans is briefly described and compared with disease progression in routinely used animal models. The relevance of findings obtained in animal models of AD is also discussed with respect to AD pathology in humans. Further, this review summarizes recent findings regarding the role/participation of glial cells in pathogenesis of AD, focusing on changes in their morphology, functions, proteins and gene expression profiles. As for astrocytes and microglia, they are fundamental for the progression and outcome of AD either because they function as effector cells releasing cytokines that play a role in neuroprotection, or because they fail to fulfill their homeostatic functions, ultimately leaving neurons to face excitotoxicity and oxidative stress. Next, we turn our attention towards NG2 glia, a novel and distinct class of glial cells in the central nervous system (CNS), whose role in a variety of human CNS diseases has begun to emerge, and we also consider the participation of oligodendrocytes in the pathogenesis and progression of AD. Since AD is currently an incurable disease, in the last part of our review we hypothesize about possible glia-oriented treatments and provide a perspective of possible future advancements in this field.

Association of Apolipoprotein E (ApoE) Polymorphism with Alzheimer's Disease in Chinese Population by Lingling Zheng, Jianzhong Duan, Xiaoling Duan, Weitao Zhou, Chunjiang Chen, Yanhua Li, Jie Chen, Weihui Zhou, Yan-Jiang Wang, Tingyu Li, Weihong Song (912-917).
Apolipoprotein E (ApoE) plays a vital role in cholesterol metabolism and its allele polymorphisms have been associated with several diseases including Alzheimer's disease (AD). There are few systematic studies on ApoE polymorphism and its association with AD in Chinese population. To examine this issue, participants included 4251 subjects and 404 AD patients with 390 healthy elderly residing in Chongqing city were genotyped. The results showed that the ?3 allele presented the highest frequency (82%), followed by ?4 (6.25%) and ?2 (11.75%) in general population. ?3/?3 genotype carriers are the most common ones (64.19%) and the ?4/?4 had the lowest frequency (0.59%). The frequency of ApoE?4 allele frequency in AD (15.35%) was significantly higher than control (10.00%). Those carriers of two ?4 allele have five time higher risk to develop AD. Our study demonstrate that ApoE?4 allele is a risk factor of AD for Chinese population.

ApolipoproteinE4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and as such is a promising therapeutic target. This study examined the extent to which the pathological effects of apoE4 can be counteracted in vivo utilizing an immunological approach in which anti-apoE4 antibodies are applied peripherally by i.p. injections into apoE4-targeted replacement mice. Prerequisites for the successful pursuit of this objective are the availability of antibodies that specifically bind brain apoE4 and not apoE3, and demonstrating that direct application of these antibodies into the brain can counteract the effects of apoE4. Accordingly, it was shown that the antiapoE4 monoclonal antibody (mAb) 9D11 binds specifically to brain apoE4 and not apoE3. Direct i.c.v. application of mAb 9D11 prevented the apoE4-driven accumulation of A? in hippocampal neurons following activation of the amyloid cascade by inhibiting the A?-degrading enzyme neprilysin. These findings provide a proof-of-concept that anti-apoE4 mAb 9D11, when introduced into the brain, can counteract the apoE4 effects in vivo. Subsequent experiments, utilizing repeated i.p. injections of mAb 9D11, resulted in the formation of apoE/IgG complexes specifically in apoE4 mice. This was associated with reversal of the cognitive impairments of apoE4 in the Morris water maze and the novel object recognition test as well as with reversal of key apoE4-driven pathologies including the hyperphosphorylated tau and the reduced levels of the apoER2 receptor. These results indicate that anti-apoE4 immunotherapy counteracts the cognitive and brain pathological effects of apoE4, and suggest that such an approach could also benefit human apoE4 carriers.

Mitochondrial Respiration in the Platelets of Patients with Alzheimer's Disease by Zden|k Fišar, Jana Hroudová, Hana Hansíková, Jana Spá|ilová, Petra Lelková, László Wenchich, Roman Jirák, Martina Zv||ová, Ji|í Zeman, Pavel Martásek, Ji|í Raboch (930-941).
Mitochondrial dysfunctions significantly contribute to the pathogenesis of Alzheimer's disease (AD). Here, we studied the relationship between AD and changes in the mitochondrial rates of respiration in blood platelets, respiratory chain complexes activity, and coenzyme Q10 plasma concentrations. In intact platelets obtained from AD patients, we observed a decrease in endogenous basal respiration rates, a decrease in the maximal capacity of the electron transport system (ETS), and higher respiratory rates after inhibiting complex I of the ETS. When normalized for citrate synthase activity, rotenone inhibited respiratory rates and complex I activity was significantly altered. In permeabilized platelets, mitochondrial respiration was completely rescued by the addition of complex I substrates. The changes in mitochondrial respiratory parameters were not associated with the progression of AD except for the capacity of the ETS in permeabilized platelets. In AD, complex I activity was increased, complex IV activity was decreased, and coenzyme Q10 plasma concentrations were decreased. Our data indicate that both insufficiency in substrates entering into the oxidative phosphorylation system and functional disturbances in the ETS complex are responsible for the decrease in respiration observed in intact platelets in AD patients. Analyses of complex IV activity, the respiratory rates of intact platelets, and the capacity of the ETS in permeabilized platelets may enable the characterization of mitochondrial dysfunctions in the initial stage of AD.

Influence of Genetic Background on Apathy-Like Behavior in Triple Transgenic AD Mice by R. Pardossi-Piquard, I. Lauritzen, C. Bauer, G. Sacco, P. Robert, F. Checler (942-949).
Apathy is an early and common neuropsychiatric syndrome in Alzheimer's disease (AD) patients. In clinical trials, apathy is associated with decreased motor activity that can be monitored by actigraphy. The triple transgenic mouse AD model (3xTgAD) has been shown to recapitulate the biochemical lesions as well as many of the synaptic and cognitive alterations associated with AD. In the present work we found that these mice also develop an early and consistent apathy-like behavior as evidenced by a drastic decrease in spontaneous activity measured by actimetry. We recently established that these mice also display an intraneuronal accumulation of the ?-secretase-derived ?APP fragment (C99) appearing early, in absence of A?. Interestingly, we found that the apathy-like behavior observed in 3xTgAD mice was temporally associated with C99 accumulation and synaptic alterations. Since it is well known that the genetic background can strongly influence behavior and can induce transcriptional variability in animal models, we decided to determine the influence of genetic background on the above-described alterations. We backcrossed 3xTgAD mice to C57BL/6 and found that the genetic background had no influence on either C99 accumulation or synaptic plasticity alterations, but strongly affected the apathy-like behavior.