Memory Cure: How to Protect Your Brain Against Memory Loss and Alzheimers Disease 2004 Edition

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In the clinical context we use neuropsychological test batteries like the CERAD Consortium to Establish a Registry for Alzheimer's Disease examination, the Mini-Mental State examination, and various other test constructs and scales, like the clinical dementia rating scale, that investigate different aspects of memory over a broad range of various cognitive domains. AD patients typically display a cognitive profile with impairments in multiple cognitive domains. This cognitive profile develops over time, and AD patients often start to show a progressive decay of working memory.

The patients display increased sensitivity to distraction in memory tasks, the capacity of working memory measured, eg, digit span is, however, at first still intact. Interestingly, the medications used currently to treat AD like acetylcholinesterase inhibitors or memantine work partly by increasing attention and concentration and work mainly in mild-to-moderate AD. The deficits in attention and working memory associated with damage to frontal subcortical circuits also influence executive functions in AD, impairing planning, problem solving, and goal-directed behavior such as the ability to deploy response alternatives or modify behavior.

AD patients show impaired results in tests that require planning, problem solving, or cognitive flexibility, eg, the Wisconsin Card Sorting Test, the Stroop test, or the Tower of London Test. The manifestation of impairment in such tests of executive functioning corresponds to the onset of difficulties in the performance of daily activities in these patients and marks the progression to the state of full dementia. The Boston Naming test assesses the ability to name pictures of objects through spontaneous responses, and the need for various types of cueing.

Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with mild cognitive impairment. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria. AD patients show early difficulties in visuospatial processing and conceptual errors like misrepresentation of numbers in the command, but not in the copy, condition, pointing to deficits in semantic memory.

It consists of two parts in which the subject is asked to connect a set of 25 dots as fast as possible while maintaining accuracy. Visual search speed, scanning and processing abilities, mental flexibility, and executive functioning can be assessed with this test. Regarding animal models, there are plenty of paradigmata available to test memory functions, but there is an overall lack of validated animal data that can be aligned with similar tests in human settings.

Snigdha et al started with the comprehensive toolbox for Neurologic Behavioral Function from the National Institutes of Health NIH which contains evaluated tests for cognitive, motor, sensory, and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age and analyzed strengths and limitations of available animal behavioral tests to find matches.

They defined a preclinical battery that aims to parallel the NIH Toolbox, and may help to close the gap between data from different species. An international task force is, however, working on standard operating procedures that would enable comparable study designs. Subjective cognitive impairment is defined as the individual coming up with the mere feeling that something is not in order, without any objective parameters supporting that notion in the first place. Such a stage labeled subjective cognitive impairment may precede mild cognitive impairment in the continuum of Alzheimer disease manifestation.

Using such a definition and without objective neuropsychological test alterations, the atrophy pattern of patients with subjective cognitive impairment seem to be related to the atrophy pattern seen in AD. Their gray matter volume was reduced in the right hippocampus. At follow-up, these patients showed poorer performance on measures of episodic memory. The observed memory decline was associated with reduced glucose metabolism in the right precuneus at baseline.

The authors conclude that their concept of subjective memory impairment may define the earliest clinical manifestation of AD. They showed a reduction in right hippocampal activation during episodic memory recall, still in the absence of performance deficits. This was accompanied by increased activation of the right dorsolateral prefrontal cortex.

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No such differences in performance and brain activation were detected for working memory. This may indicate subtle early neuronal dysfunction on the hippocampal level and compensatory mechanisms that preserve memory performance. Regarding ApoE4, cognitively unimpaired young elderly with and without subjective memory impairment were tested on episodic memory and on tasks of speed and executive function. Medial temporal lobe volumetric measures were calculated from MRI images. In the subjective memory impairment group, ApoE4 carriers performed worse on the episodic memory and showed smaller left hippocampal volumes.

The interaction of group and ApoE genotype was significant for episodic memory and right and left hippocampal volumes. The negative effect of ApoE4 on episodic memory and hippocampal volume in the group suffering from subjective memory decline also supports the notion that this may be a prodromal condition of AD. Impaired sense of smell or hyposmia is one of the earliest clinical features in neurodegenerative disorders like both AD or Parkinson's disease. A recent meta-analysis of 81 studies indicated that AD and PD patients are more impaired on odor identification and recognition tasks than on odor detection threshold tasks.

AD patients were found to be more impaired on higher-order olfactory tasks involving specific cognitive processes. The impairment of smell recognition is of clinical importance, as patients often report malodorous sensations and changes in, eg, the taste of foods leading to behavioral alterations. Consequences may range from increasing malnutriton to the development of delusions of poisoning that may trigger aggressive behavior.

The incidence of unprovoked seizures is clearly higher in sporadic AD than in reference populations with implications for memory functions. Nonconvulsive epileptiform activity could underlie at least some of the cognitive impairments observed in AD. Up to 1 in 5 patients with sporadic AD has at least 1 unprovoked clinically apparent seizure during their illness, and clinical guidelines recommend obligatory treatment for this condition.

The risk of epileptic activity is greater in early-onset AD. Many mutations in the presenilin-1 gene are associated with epilepsy. Many patients with AD show fluctuations in cognitive functions such as transient episodes of amnestic wandering or disorientation. While an intermittent inability to retrieve memories cannot be easily explained by relatively protracted processes such as neuronal loss, plaque deposition, or tangle formation, an abnormal epileptic activity of neuronal networks can. Extensive work in this field was published by the group of Lennart Mucke.

This leads to changes in the texture of the neural networks involved and might explain disruptions of the networks as seen in the default mode network DMN in AD. AD affects the default mode network DMN. This network comprises brain regions that are active and interconnected in a wakeful state when the mind is not focused on something specific. Anatomically it includes part of the medial temporal lobe, the medial prefrontal cortex, the posterior cingulate cortex, ventral precuneus, and the medial, lateral, and inferior parietal cortex. This networks develops during childhood and adolescence and reaches full integration in adults, characterized by coherent infraslow EEG oscillations smaller than 0.

The DMN is linked to other low-frequency resting state networks in the brain and is anti-correlated with the ventral and dorsal attention network. When AD patients undergo a FDG-PET the pattern of hypometabolism often mirrors the same regions that belong to the posterior parts of the DMN, namely the posterior cingulate cortex, the retrosplenial cortex, inferior parietal lobule, and the lateral temporal cortex. Interestingly, ApoE4 carriers have also been found to have a higher rate of activity in the DMN at rest compared with ApoE2 or ApoE3 carriers, and decreased connectivity.

Indeed, there are some studies that may support such a link. A further supporting observations come from a new PET method of mapping glycolysis based on measuring the ratio of oxygen to glucose consumption. Vlassenko et al calculated the spatial distribution of the regional glucose use apart from that entering oxidative phosphorylation. The map of resting-state glycolysis correlated remarkably well with the distribution of amyloid plaques. Here only partial network involvement was observed, with apparent decoupling of frontal areas from the DMN 80 An important study by Kang et al used in vivo micro-dialysis in mice and found that the amount of pamyloid in the interstitial brain fluid correlated positively with wakefulness.

Sleep and the functional connectome are overlapping research areas. Such infraslow oscillations may organize sleep-dependent neuroplastic processes including consolidation of episodic memory, for example. Picchioni et al found positive correlations between the power in the infraslow EEG band and MRI blood oxygen level-dependent BOLD response in subcortical regions and negative correlations in the cortex.

Robust negative correlations were detected principally in paramedian heteromodal cortices whereas positive correlations were seen in cerebellum, thalamus, basal ganglia, lateral neocortices, and hippocampus. Our understanding of DMN activity and its regulation during sleep may be also important for our general understanding of phenomena like memory, arousal, and consciousness.

Sleep changes in patients with amnestic mild cognitive impairment may contribute to memory deficits by interfering with sleep-dependent memory consolidation.

alzheimers causes

In a small study, Ju investigated sleep in cognitively healthy probands older than 45 years. This group had worse sleep quality, as measured by sleep efficiency compared with those without amyloid deposition, after correction for age, sex, and ApoE4 allele carrier status, while the quantity of sleep did not differ between groups. Frequent napping, 3 or more days per week, was associated with amyloid deposition.

The authors concluded that indices for amyloid deposition in the preclinical stage of AD appears to be associated with worse sleep quality. Taken together the brain activity patterns may directly modulate the molecular cascades that are relevant to diseases. In the case of AD, increased resting-state activity may accelerate the formation of amyloid pathology.

This opens up perspectives for new interventions that may take the form of a therapy that attempts to modify glycolysis or other aspects of brain metabolism or to boost prophylaxis by the promotion of healthy sleep behavior or working behavior. For the clinician the easily applicable neuropsychological test batteries augmented by a test for olfactory recognition continue to be at the heart of the diagnostic process for dementias, although new methods like CSF analyses or MRI volumetry are increasingly available and validated for clinical use.

Despite enormous progress in our knowledge of some pathophysiologic mechanisms in the last decade, we are still far from understanding AD and also probably from finding a cure. The available medications or medications may, however, help us to manage some symptoms for our patients, and gain some time for them. To date the recent scientific advancements primarily offer earlier diagnosis. With new diagnostic criteria properly applied, we will likely be able to diagnose Alzheimer's disease many years before any relevant impairment is experienced by the patient. Perhaps CSF tau concentrations could be helpful, but at the moment only time will tell us the individual course of the disease.

National Center for Biotechnology Information , U. Journal List Dialogues Clin Neurosci v. Dialogues Clin Neurosci. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease AD and by their caretakers. Keywords: memory , Alzheimer's disease , neuropsychological test , brain atrophy , default mode network.

Atrophy in AD The neuropathological hallmarks of the atrophy process in AD are the presence of senile plaques amyloid deposits and neurofibrillary tangles in autopsied brains. Open in a separate window. Figure 1. Atrophy in a case of AD over 4 years.

Courtesy of L. Impact of new diagnostic criteria Recently workgroups of the Alzheimer's Association and the National Institute on Aging have issued new criteria and guidelines to diagnose Alzheimer's disease supplanting the previous guidelines first published in The neuropsychology of AD: tests and what they indicate Consensus exists that AD starts clinically with memory complaints, which may affect episodic memory, speech production, with naming or semantic problems, or visual orientation. Memory of smell Impaired sense of smell or hyposmia is one of the earliest clinical features in neurodegenerative disorders like both AD or Parkinson's disease.

AD and epileptic activity The incidence of unprovoked seizures is clearly higher in sporadic AD than in reference populations with implications for memory functions. Sleep and memory Sleep and the functional connectome are overlapping research areas. Conclusion For the clinician the easily applicable neuropsychological test batteries augmented by a test for olfactory recognition continue to be at the heart of the diagnostic process for dementias, although new methods like CSF analyses or MRI volumetry are increasingly available and validated for clinical use.

Wimo A. An estimate of the worldwide prevalence and direct costs of dementia in Dement Geriatr Cogn Dis. Hebert LE. Alzheimer A. Blennow K. Alzheimer's disease. Gerrish A. J Alzheimers Dis. Williams GC. Pleiotropy, natural selection, and the evolution of senescence. Mayeux R.

Gene-environment interaction in late-onset Alzheimer disease: the role of apolipoprotein-epsilon4. Alzheimer Dis Assoc Disord. Fullerton SM. Am J Hum Genet. Bufill E. Apolipoprotein E polymorphism and neuronal plasticity. Am J Hum Biol. Finch CE. Meat-adaptive genes and the evolution of slower aging in humans. Q Rev Biol. Braak H. Neurofibrillary changes confined to the entorhinal region and an abundance of cortical amyloid in cases of presenile and senile dementia.

Acta Neuropathologica. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathology. Neuropathological staging of Alzheimer-related changes. Hyman BT. Alzheimers-disease - cell-specific pathology isolates the hippocampal formation. Vulnerability of select neuronal types to Alzheimer's disease. Ann N Y Acad Sci. Bondareff W. Loss of neurons of origin of the adrenergic projection to cerebral cortex nucleus locus ceruleus in senile dementia.

Mann DM.

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A comparison of changes in the nucleus basalis and locus caeruleus in Alzheimer's disease. J Neurol Neurosurg Psychiatry. Jacobs HI. Atrophy of the parietal lobe in preclinical dementia. Brain Cogn. Parietal cortex matters in Alzheimer's disease: an overview of structural, functional and metabolic findings.

Neurosci Biobehav Rev. Curr Alzheimer Res. Fox NC. Visualisation and quantification of rates of atrophy in Alzheimer's disease. Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease: power calculations and estimates of sample size to detect treatment effects.

Arch Neurol. Andrews KA. Pictures of plaques were taken just after the labeling, counted manually and analysed dividing the number of plaques by the number of sections analysed. To ensure equal protein loading, the Ponceau method was used to stain the membranes before probing with the antibodies [ 21 ]. The membranes were washed and then incubated with a secondary biotinylated-antibody horseradish peroxidase-conjugated Goat-anti-Rabbit IgG, diluted in TBST for 2 hours at room temperature. After deteccion, membranes were stripped with stripping buffer mM glycine, 0. The density of immunoblotting was quantified with image J software [ 22 ].

Since brain samples were divided in order to allow histological and molecular analysis, in some experiments the number of replicates n were on the low side. All analysis were done using StatSoft, Inc. The motivation of this work to investigate the preventive and therapeutic effects of microdose lithium in transgenic mice for AD, focusing on its molecular effects, was based on previously reported neuroprotective mechanisms of lithium and its toxicity in weight-based dosing [ 6 , 10 ], mainly in the elderly. Moreover, this work follows on previous results with the microdose of lithium 1.

Lithium was administered as lithium carbonate in the dose 1. The concentration of lithium to be dissolved in water during all the observation time, as long as the necessity of dose adjustment during the period, were determined according to mice water consumption. Detection of a significant diference in the ingested volume of water of treated versus untreated animals is important to advise possible renal toxicity, which will lead to increases in water comsumption [ 23 ].

However, no significant difference was observed in water ingestion between lithium treated and untreated groups data not shown. Among WT mice, only two animals died between 12 and 18 months of age, indenpendent on the treatment they were submitted to. The behavioural tests used in this project depend on good locomotor activity, as animals need to explore the mazes and equipment to have their behavior evaluated. In order to verify if lithium microdose interfered with this activity, animals were submitted to mobility tests at 6 and 18 months of age. Treatment of TG mice with lithium did not change their locomotor activity as well Fig 2B.

It has been reported that transgenic animal models for Alzheimer disease present greater motoractivity in open field and object recognition tasks. This can be due to cortical and hippocampal atrophy in some of those animals [ 24 , 25 , 26 ]. However, this increase in locomotion was not verified in the present work. In WT groups, treatment with lithium did not influence locomotion S1 Fig.

Anxiety, a common disorder observed in AD patients [ 27 ], was evaluated to verify if the lithium treatment could alter this behavior. Elevated plus maze is a test whose foundation is based on the conflict between the natural tendency of rodents to explore a novel environment versus the natural tendency to avoid narrow elevated open areas [ 28 ]. In our experiments, we measured this behavior as the ratio of the number of entries in open arms over the number of entries in closed arms and also the ratio of time spent in open arms over time spent in closed arms.

In our experiments, however, these behaviours were not observed. Nevertheless, other works [ 31 ] showed that treatment with lithium was effective to control anxiety in rats. In line with this description, in the present work an increase in anxiolytic-like behavior was observed. This suggests that lithium microdose may turn the general behavior to a calmer state, which may contribute in a chronic treatment to the efficacy of the pharmacological strategy.

In this way, stress level is lower and this method is being used as an alternative to Morris water maze [ 32 ]. Hippocampus and some areas of the brain cortex are recruited during spatial memory formation and recovery. In this way, mice and rats with hippocampal lesions present decreased performance in Barnes maze [ 33 ]. Animals were submitted to the equipment twice a day, for 5 days, when they were 6 months old. Fig 3A. In the following months, spatial memory was evaluated every 3 months using the same protocol.

Fig 4A. It is important to point out that the improvement in behavior of TG Li16 can be due to improvements in the learning process, since those animals began the treatment with lithium four months before the training session. On the other side, the observed inprovement in TG Li8 may be related to better consolidation or retrieve of memory, since they learned the task at 6 months of age and the treatment began when they were 10 months old.

This is remarkable information, as lithium microdose can be efficient to improve learning, memory consolidation and information retrieval. In the WT group, animals from both treatment times with lithium maintained spatial memory along the observed period S3 Fig. Animals were first submitted to Barnes Maze when they were 6 months old, and we used a five-day protocol, exposing the animal twice a day to the task Acquisition Session ; latency was recorded.

Animals were re-exposed to the protocol every 3 months and TG Ctrl could not retain the memory, as its latency rose in test 2 at 12 months of age and kept higher than the latency of WT group up to the end of the experiments A. We next compared the three TG groups and all of them learned the task, at 6 months of age Acquisition Session. In addition, distance covered to find the escape box and time spent in the target quadrant was evaluated in the last test, when animals were 18 months old.

There was no difference in the distance covered by all groups. Nevertheless, regarding the time spent in the target quadrant, it was observed that TG Ctrl animals spent significant less time in the target quadrant However, the treatment with lithium for 8 or 16 months increased that time, a significant difference being observed in animals treated for 16 months There was no difference in this behavior concerning WT animals treated with lithium S4 Fig. At 18 months of age the time spent in the target quadrant during the last Barnes maze test was evaluated. Control TG animals spent less time in the quadrant where the escape box was located.

So, treatment with lithium since 2 months of age until the elderly was effective in maintaining spatial memory of mice with or without neurodegeneration. Aversive-related memory was evaluated in inhibitory avoidance equipment when animals were 18 months old. Two sessions were performed acquisition session—AS, and test session—TS , with a 24h time separating them.

Initially, acquisition session of WT Ctrl and TG Ctrl were compared and it was verified that they were significantly different. Latency of TG Ctrl [ Treatment with lithium for 8 or 16 months significantly reduced the time to enter the dark side in AS [ This type of memory was evaluated using an inhibitory avoidance apparatus in which animals were placed in a light box with access to a dark one, where they received a shock on the paws. The latency max. Test session TS was performed 24 hours after acquisition session AS. Data plotted are median and interquartile range. In test session, it was observed that WT Ctrl animals were clearly able to remember the task, since latency to enter the dark box was significantly higher in the TS [ Although some mice may remember the task and maybe that is the reason why TS from WT Ctrl and TG Ctrl were not statistically different , the majority did not recognize and did not remember that the dark side of the shuttle box as aversive..

Treatment with lithium for 8 or 16 months significantly increased the latency to enter the dark side of the box by 7. With these observations, it is possible to suggest that lithium treatment in microdose protects different types of memory processing from degradation. As mentioned before, our research team has already shown that the use of this microdose prevented memory deficit in human subjects. However, the effects were evident after a minimum of three months treatment [ 5 ]. This is probably due to some important brain adaptations that occur during the healing or protection process in the presence of lithium, as decribed next.

Neuroplasticity involves structural changes that may lead to functional improvements, which can explain the behavioral changes observed with the lithium treatment. In this way, the density of neurons was evaluated in the hippocampus and prefrontal cortex using an antibody for NeuN protein. In the same way, treatment with lithium did not change the density of NeuN in these areas data not shown. However, in the granular layer of the dentate gyrus GrDG , a significant reduction of Brains sections were immunolabeled with NeuN antibody. The coronal sections shown are at approximately the same anatomical level left panels 1.

Representative images are from samples run in the same batch during immunohistochemistry procedure. Images in each row belong to the same animal and match with the animals showed on panels of thioflavine-S staining figure. Figure abbreviations for cortical areas: Fr3, frontal cortex, area3; M1, primary motor cortex; M2, secondary motor cortex; Cg1, Cingulate cortex, area1; PrL, prelimbic cortex; IL, infralimbic cortex. These observations are in line with others that already described that lithium increases neurogenesis in the sub-granular zone of GrDG and prevents hippocampal apoptosis [ 36 — 37 ].

The hippocampus is highly recruited in this task and GrDG is involved in memory events that can be predicted by the animal [ 38 — 39 ] in order to navigate in a place that rescues spatial memory. For this, GrDG cells receive inputs from the entorhinal cortex perforant pathway [ 40 ]. GrDG acts like a learning net that withdraws input redundancies sensorial inputs such as vestibular, olphactory, visual, audictive and somatosensorial leading to more categorized outputs to be used in CA3 [ 41 ].

In this way, one can solve separation patterns of spatial clues [ 42 ]. GrDG plays an important role in data codification, helping to build spatial representations for posterior CA3 area. Preservation in neuronal density in GrDG can also be associated with the anxiolytic effect observed in mice treated with lithium in the elevated plus maze test. Inputs to GrDG can reduce anxiety without affecting the learning process [ 43 ].

Figs 7C and 8A and 8C. The prefrontal cortex is endowed with the expression of remote memories and the cingulate cortex, specifically, is directly related to the formation and retrieval of remote spatial memory [ 44 , 45 ] and with the hippocampus coordinated spatial memory [ 46 ]. During aging, neuronal activity is spread in the prefrontal cortex of both hemispheres as a system of compensation against neurodegenerative changes that may occur along the process [ 47 ]. Also, prefrontal region interacts functionally with both the ventral and dorsal brain.

This area is being implicated as a neural center for attention driven by stimulus and objectives [ 48 ]. Besides the neuronal density, the preservation of synaptic terminals was also verified using an antibody against synaptophysin p38 which is a transmembrane glycoprotein located in pre-synaptic vesicles [ 49 ]. A decrease in synaptophysin density was described earlier in this murine model of neurodegeneration [ 12 ], however, in the present study no difference between WT Ctrl or TG Ctrl animals was observed S7 Fig. In the same way, the treatment with lithium made no difference in the density of this protein.

This phenomenon was observed earlier by our group [ 50 ] and others where no significant difference in synaptophysin western-blotting between APP23 mice and wild-type controls were verified at 3 and 25 months of age [ 51 ] and could be explained by the enlargement of synaptic size to compensate de decrease in synapse number [ 52 , 53 ]. Also, the abscense of synaptophysin decrease could be related to a recognized trophic effect of APP contributing to a compensatory mechanism preventing or delaying the synaptic loss in face of the neuronal loss [ 54 ].

Still focusing on neuroplasticity, brain-derived neurotrophic fator BDNF was quantified in total hippocampus and cortex. This protein is involved in synaptic changes that occur during long-term potentiation and, as a consequence, in long-term memory formation [ 55 ]. In the present study, although the analysis of BDNF density in hippocampus and cortex were performed with only three samples of each group, some preliminary and exciting findings can be described.

In the same way, no difference in hippocampus was observed with the treatment of animals with lithium Fig 9B. Probably the maintenance of neuronal bodies in cortex was promoted by the increase in neurogenesis, with increase in BDNF. This neurotrophin also stimulates activation of endothelial nitric oxide synthase eNOS which promotes NO increase in neural stem cells that reciprocally regulate BDNF expression. This mechanism was verified after cerebrovascular accident in mice [ 60 ]. In the hippocampus, the observed neuroprotection may be related to other molecular mechanisms [ 61 ], but BDNF.

One probable molecular pathway for the neuroprotection promoted by lithium chronic treatment is the protection against excitoxicity induced by glutamate mediated by NMDA receptors, as lithium can inhibit calcium influx through NMDA receptors [ 62 , 63 ]. Also, it was already described that lithium treatment can induce survival molecules in the frontal cortex, such as Bcl-2, an anti-apoptotic protein that inhibits the release of cytochrome-C from mitochondria, regulating permeability of the external mitochondrial membrane [ 64 , 65 ].

Besides, lithium can also keep homeostasis in endoplasmatic reticulum and induce neurogenesis by inhibition of GSK-3 protein and activation of ERK cascades [ 66 , 67 ]. Neuroprotection was also verified determining the potential of the treatment with lithium microsode to inhibit the formation of senile plaques.

They are composed of a central core with amyloid fibrils surrounded by dendrites, distrophic axon terminals and activated microglia [ 68 ]. In this work a great number of plaques were observed in the brain of transgenic animals [ The treatment with lithium for 8 months, decreased the number of plaques in TG mice, but it was not significant Figs 10B and 11E and 11F.

Brains sections were stained with Thioflavine-S and plaques were counted in the whole section. Data were plotted in median and interquartile range. The coronal sections shown are at approximately the same anatomical level Representative images are from samples run in the same batch during staining procedure. Images match with the animals showed on Fig 8. Structure abreviations were cited according to Franklin and Paxinos, [ 69 ]. Inhibition of plaque formation seemed to be essential to the observed behavioural alterations, as deposition of plaques in hippocampus has already been associated to changes in behavior of mice [ 70 ] and humans [ 71 ].

One of the most known pathways related to formation and pathogenicity of amyloid plaques is GSK3 pathway. Although not tested in the present work, other hypothesis that can be involved with the molecular mechanism of amyloid plaques formation or degradation is the autophagy and the increase in oxidative stress. Autophagy is a process that is negatively regulated by mTOR and positively regulated by inhibition of inositol monophosphatase; both of them may be regulated by chronic treatment with lithium [ 75 , 76 ].

GSK-3 family was highly conserved along the evolution. This enzyme family has an important role in cellular survival and apoptosis [ 79 ]. Lithium is the major inhibitor of these enzymes. It induces phosphorylation in inhibitory serine sites [ 80 , 81 , 82 ] and evaluation of the enzymes activity is critical for the understanding of lithium effects. With this microdose, no statistical difference was observed in this activity in both areas S9 Fig. Also, GSK-3 plays an important role in various aspects of the regulation of glucose transport and metabolism.

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In this way, the decrease in GSK-3 activity could lead to a pathological increase in intracellular concentration of glucose [ 87 ]. Recently it was shown that long-term lithium treatment reduces glucose metabolism in the cerebellum and in the hippocampus of nondemented older adults. These alterations were not associated with any clinical evidence of toxicity and clinical implications need to be clarified [ 88 ].

In the present work, considering the treatment duration, slight differences in the activity of this enzyme could happen and contribute to the general improvement in cerebral functioning in TG mice. More studies are needed to confirm this hypothesis. This work is the first to show that chronic microdose lithium treatment can prevent memory deficits caused by progressive neurodegeneration. Protection of both aversive-related and spatial memories was observed, making their behavior similar to that observed in age-matched controls.

This improvement was correlated to neuroprotection, as lithium protected the neuronal loss in the hippocampus and increased the density of neurons in the prefrontal cortex. This could be related to improvement in attention and memory retention along treatment. Treatment with lithium also increased BDNF density in the cortex which accounts for advances in neuronal communication that is surelly degraded in neurodegenerative processes.

This degration is also related to the presence of senile plaques. Plaques density was significantly reduced with the chronic treatment with lithium. It is possible that microdose lithium has suppressed expression of the APP transgene in TG mice which would explain most of the results presented here.

Although this hypothesis was not tested, it cannot be totally excluded. Taking together, these data reinforce the protective effect of lithium already observed in human subjects. In the same way, lithium treatment did not influence synaptic density in both WT or TG groups. Authors want to thank Dr. Wagner Montor for English review. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders.

This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: All relevant data are within the paper and its Supporting Information files.

Introduction Demographic changes resulting from the increase in life span and the increasing number of aged people lead to a dramatic increase in the prevalency of dementias. Materials and Methods 1. Animals Male hemizygous transgenic mice—here called TG—B6. Treatment Animals were divided in groups of transgenic and non-transgenic animals treated or not with lithium. Behavioural Tests 3. Evaluation of Locomotor Activity. Evaluation of Spatial Memory. Evaluation of anxiety.

Evaluation of aversive-related memory. Download: PPT. Evaluation of neuronal bodies density. Quantification of senile plaques. Determination of BDNF density. Results and Discussion 1. General observations The motivation of this work to investigate the preventive and therapeutic effects of microdose lithium in transgenic mice for AD, focusing on its molecular effects, was based on previously reported neuroprotective mechanisms of lithium and its toxicity in weight-based dosing [ 6 , 10 ], mainly in the elderly.

Mobility The behavioural tests used in this project depend on good locomotor activity, as animals need to explore the mazes and equipment to have their behavior evaluated. Fig 2. Treatment with lithium did not interfere in motor activity of the animals, both WT and TG. Evaluation of anxiety Anxiety, a common disorder observed in AD patients [ 27 ], was evaluated to verify if the lithium treatment could alter this behavior. Fig 3. Lithium treatment reduces anxiolytic behavior in TG mice. Fig 4. Lithium treatment prevents the loss of spatial memory in TG mice.

Fig 5. Lithium treatment increased the time spent in the target quadrant in Barnes maze. Evaluation of aversive-related memory Aversive-related memory was evaluated in inhibitory avoidance equipment when animals were 18 months old. Fig 6. Lithium treatment protected TG mice from losing aversive-related memory. Fig 7. Lithium treatment prevented neuronal loss in TG mice treated for 16 months in GrDG and increased the density of neurons in prefrontal cortex. Fig 8. Fig 9. Fig Lithium treatment reduced the number of amyloid plaques in TG mice.

Conclusion This work is the first to show that chronic microdose lithium treatment can prevent memory deficits caused by progressive neurodegeneration. Supporting Information. S1 Fig. Treatment with lithium did not influence locomotion of WT animals.

Dementia symptoms

S2 Fig. Treatment with lithium can reduce anxiety even in absence of neurodegeneration. S3 Fig. WT animals trated with lithium maintained spatial memory. S4 Fig. Lithium treatment did not influence the strategy to find the target in Barnes maze. S5 Fig. Lithium treatment preserved the aversive-related memory of WT mice. S6 Fig. Density of neurons was maintained in WT mice treated with lithium. S7 Fig. Lithium treatment did not influence synaptic labeling. S8 Fig. S9 Fig. Acknowledgments Authors want to thank Dr. References 1. What is normal in normal aging?

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