Impairments in spatial representations and rhythmic coordination of place cells in the 3xTg mouse model of Alzheimer's disease

Alzheimer's disease (AD) is an irreversible and highly progressive neurodegenerative disease. Clinically, patients with AD display impairments in episodic and spatial memory. However, the underlying neuronal dysfunctions that result in these impairments remain poorly understood. The hippocampus is crucial for spatial and episodic memory, and thus we tested the hypothesis that abnormal neuronal representations of space in the hippocampus contribute to memory deficits in AD. To test this hypothesis, we recorded spikes from place cells in hippocampal subfield CA1, together with corresponding rhythmic activity in local field potentials, in the 3xTg AD mouse model. We observed disturbances in place cell firing patterns, many of which were consistent with place cell disturbances reported in other rodent models of AD. We found place cell representations of space to be unstable in 3xTg mice compared to control mice. Furthermore, coordination of place cell firing by hippocampal rhythms was disrupted in 3xTg mice. Specifically, a smaller proportion of place cells from 3xTg mice were significantly phase‐locked to theta and slow gamma rhythms, and the theta and slow gamma phases at which spikes occurred were also altered. Remarkably, these disturbances were observed at an age before detectable Aβ pathology had developed. Consistencies between these findings in 3xTg mice and previous findings from other AD models suggest that disturbances in place cell firing and hippocampal rhythms are related to AD rather than reflecting peculiarities inherent to a particular transgenic model. Thus, disturbed rhythmic organization of place cell activity may contribute to unstable spatial representations, and related spatial memory deficits, in AD. © 2017 Wiley Periodicals, Inc.     

Individual differences in spatial memory among aged rats are related to hippocampal PKCgamma immunoreactivity

We reported previously that the extent of spatial memory impairment among aged rats was correlated positively with levels of protein kinase Cgamma in hippocampal homogenates measured by quantitative Western blotting (Colombo et al., 1997). In the current study, immunocytochemistry was used to test whether the relationship between elevated PKC-gamma and memory impairment among aged rats could be localized further within regions of the hippocampus. Six- and 24-month-old male Long-Evans rats were first trained in the water maze on a standard place-learning task and then trained 2 weeks later on a transfer task designed for rapid acquisition. In comparison with young rats, aged rats with impaired spatial memory had increased PKCgamma-immunoreactivity (PKCgamma-ir) in CA1 of the hippocampus, but not the dentate gyrus. In addition, PKCgamma-ir in CA1 was correlated positively with spatial memory impairment among aged rats on the standard place-learning and the transfer training tasks. The current results are consistent with our previous report of PKCgamma in hippocampal homogenates, and show further that the relationships between PKCgamma-ir and memory impairments among aged rats are most evident in area CA1. Thus age-related impairments of spatial memory, as well as deficits in the flexible use of previously acquired information, may result from dysregulation of PKCgamma.     

Hippocampal output area CA1 broadcasts a generalized novelty signal during an object‐place recognition task

Animals display an innate preference for novelty, spending more time exploring both novel objects and familiar objects in novel locations. This increase in exploration is thought to allow the animal to gather the information necessary to encode new experiences. Despite extensive evidence that increased exploration following spatial change requires the hippocampus, the pattern of hippocampal activity that supports this behavior remains unknown. We examined activity in hippocampal output area CA1 and one synapse upstream in area CA3 while freely behaving rats performed an object‐place recognition task. We found that the presence of novelty substantially altered activity in CA1, but not in CA3. During exploration of displaced familiar objects and novel objects in unexpected locations, CA1 place cells showed robust increases in firing rate. These firing rate increases persisted during sharp wave ripples, when place cell representations of previous experiences are replayed. Unexpectedly, increases in CA1 activity were not spatially restricted to regions of the environment that underwent change, indicating a generalized novelty signal. We suggest that hippocampal area CA1 broadcasts the presence of novelty, rather than signaling what is novel, and simultaneously becomes more plastic, allowing the integration of new information into previously stored memories. © 2014 Wiley Periodicals, Inc.     

Hippocampal place cells: parallel input streams, subregional processing, and implications for episodic memory

The hippocampus is thought to be involved in episodic memory in humans. Place cells of the rat hippocampus offer a potentially important model system to understand episodic memory. However, the difficulties in determining whether rats have episodic memory are profound. Progress can be made by considering the hippocampus as a computational device that presumably performs similar transformations on its inputs in both rats and in humans. Understanding the input/output transformations of rat place cells can thus inform research on the computational basis of human episodic memory. Two examples of different transformations in the CA3 and CA1 regions are presented. In one example, CA3 place fields are shown to maintain a greater degree of population coherence than CA1 place fields after a rearrangement of the salient landmarks in an environment, in agreement with computational models of CA3 as an autoassociative network. In the second example, CA3 place field appears to store information about the spatiotemporal sequences of place fields, starting with the first exposure to a cue-altered environment, whereas CA1 place fields store this information only on a temporary basis. Finally, recordings of hippocampal afferents from the lateral and medial entorhinal cortex (EC) suggest that these two regions convey fundamentally different representations to the hippocampus, with spatial information conveyed by the medial EC and nonspatial information conveyed by the lateral EC. The dentate gyrus and CA3 regions may create configural object+place (or item+context) representations that provide the spatiotemporal context of an episodic memory.     

Cognitive dysfunction after experimental febrile seizures

While the majority of children with febrile seizures have an excellent prognosis, a small percentage are later discovered to have cognitive impairment. Whether the febrile seizures produce the cognitive deficits or the febrile seizures are a marker or the result of underlying brain pathology is not clear from the clinical literature. We evaluated hippocampal and prefrontal cortex function in adult rats with a prior history of experimental febrile seizures as rat pups. All of the rat pups had MRI brain scans following the seizures. Rats subjected to experimental febrile seizures were found to have moderate deficits in working and reference memory and strategy shifting in the Morris water maze test. A possible basis for these hippocampal deficits involved abnormal firing rate and poor stability of hippocampal CA1 place cells, neurons involved in encoding and retrieval of spatial information. Additional derangements of interneuron firing in the CA1 hippocampal circuit suggested a complex network dysfunction in the rats. MRI T2 values in the hippocampus were significantly elevated in 50% of seizure-experiencing rats. Learning and memory functions of these T2-positive rats were significantly worse than those of T2-negative cohorts and of controls. We conclude that cognitive dysfunction involving the hippocampus and prefrontal cortex networks occur following experimental febrile seizures and that the MRI provides a potential biomarker for hippocampal deficits in a model of prolonged human febrile seizures.     

Combined administration of levetiracetam and valproic acid attenuates age‐related hyperactivity of CA3 place cells,reduces place field area,and increases spatial information content in aged rat hippocampus

Learning and memory deficits associated with age‐related mild cognitive impairment have long been attributed to impaired processing within the hippocampus. Hyperactivity within the hippocampal CA3 region that is associated with aging is mediated in part by a loss of functional inhibitory interneurons and thought to underlie impaired performance in spatial memory tasks, including the abnormal tendency in aged animals to pattern complete spatial representations. Here, we asked whether the spatial firing patterns of simultaneously recorded CA3 and CA1 neurons in young and aged rats could be manipulated pharmacologically to selectively reduce CA3 hyperactivity and thus, according to hypothesis, the associated abnormality in spatial representations. We used chronically implanted high‐density tetrodes to record the spatial firing properties of CA3 and CA1 units during animal exploration for food in familiar and novel environments. Aged CA3 place cells have higher firing rates, larger place fields, less spatial information content, and respond less to a change from a familiar to a novel environment than young CA3 cells. We also find that the combination of levetiracetam (LEV) + valproic acid (VPA), previously shown to act as a cognitive enhancer in tests of spatial memory, attenuate CA3 place cell firing rates, reduce place field area, and increase spatial information content in aged but not young adult rats. This is consistent with drug enhancing the specificity of neuronal firing with respect to spatial location. Contrary to expectation, however, LEV + VPA reduces place cell discrimination between novel and familiar environments, i.e., spatial correlations increase, independent of age even though drug enhances performance in cognitive tasks. The results demonstrate that spatial information content, or the number of bits of information encoded per action potential, may be the key correlate for enhancement of spatial memory by LEV + VPA. © 2015 Wiley Periodicals, Inc.     

CA3 place cells that represent a novel waking experience are preferentially reactivated during sharp wave‐ripples in subsequent sleep

A popular model of memory consolidation posits that recent memories stored in the hippocampus are reactivated during sleep and thereby transferred to neocortex for long‐term storage. This process is thought to occur during sharp wave‐ripples (SWRs) in nonrapid eye movement sleep (NREM). However, whether the hippocampus consolidates all recent memories in the same manner remains unclear. An efficient memory system may extract novel information from recent experiences for preferential consolidation. In the hippocampus, memories are thought to be stored initially in CA3. Therefore, CA3 place cells that encode novel experiences may be preferentially reactivated during SWRs in subsequent sleep. To test this hypothesis, we recorded CA3 place cells in rats during exposure to a familiar and a novel environment and during subsequent overnight sleep. We found that CA3 place cells that preferentially coded a novel environment showed larger firing rate increases during SWRs in NREM than place cells that preferentially coded a familiar environment. Moreover, CA3 place cell ensembles replayed trajectories from a novel environment during NREM with higher fidelity than trajectories from a familiar environment. Together, these results suggest that CA3 representations of novel experiences are preferentially processed during subsequent sleep.     

Spatial coding and physiological properties of hippocampal neurons in the Cornu Ammonis subregions

It is well‐established that the feed‐forward connected main hippocampal areas, CA3, CA2, and CA1 work cooperatively during spatial navigation and memory. These areas are similar in terms of the prevalent types of neurons; however, they display different spatial coding and oscillatory dynamics. Understanding the temporal dynamics of these operations requires simultaneous recordings from these regions. However, simultaneous recordings from multiple regions and subregions in behaving animals have become possible only recently. We performed large‐scale silicon probe recordings simultaneously spanning across all layers of CA1, CA2, and CA3 regions in rats during spatial navigation and sleep and compared their behavior‐dependent spiking, oscillatory dynamics and functional connectivity. The accuracy of place cell spatial coding increased progressively from distal to proximal CA1, suddenly dropped in CA2, and increased again from CA3a toward CA3c. These variations can be attributed in part to the different entorhinal inputs to each subregions, and the differences in theta modulation of CA1, CA2, and CA3 neurons. We also found that neurons in the subregions showed differences in theta modulation, phase precession, state‐dependent changes in firing rates and functional connectivity among neurons of these regions. Our results indicate that a combination of intrinsic properties together with distinct intra‐ and extra‐hippocampal inputs may account for the subregion‐specific modulation of spiking dynamics and spatial tuning of neurons during behavior. © 2016 Wiley Periodicals, Inc.     

Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats

Substantial information is available concerning the influence of global hippocampal lesions on spatial learning and memory, however the contributions of discrete subregions within the hippocampus to these functions is less well understood. The present investigation utilized kainic acid to bilaterally lesion specific areas of the rat hippocampus. These animals were subsequently tested on a spatial orientation task using a circular water maze, and on an associative/contextual task using passive avoidance conditioning. The results indicate that both the dorsal CA1 and the ventral CA3 subregions play important roles in learning. Specifically, CA1 lesions produced a deficit in the acquisition of the water maze task and a significant memory impairment on the passive avoidance task. CA3 lesions also caused learning deficits in the acquisition of the water maze task, and produced even greater impairments in performance on the passive avoidance task. We conclude that CA1 and CA3 hippocampal subregions each play significant roles in the overall integration of information concerning spatial and associative learning.     

Acute nicotine treatment prevents rem sleep deprivation‐induced learning and memory impairment in rat

Rapid eye movement (REM) sleep deprivation (SD) is implicated in impairment of spatial learning and memory and hippocampal long‐term potentiation (LTP). An increase in nicotine consumption among habitual smokers and initiation of tobacco use by nonsmokers was observed during SD. Although nicotine treatment was reported to attenuate the impairment of learning and memory and LTP associated with several mental disorders, the effect of nicotine on SD‐induced learning and memory impairment has not been studied. Modified multiple platform paradigm was used to induce SD for 24 or 48 h during which rats were injected with saline or nicotine (1 mg kg^?1 s.c.) twice a day. In the radial arm water maze (RAWM) task, 24‐ or 48‐h SD significantly impaired learning and short‐term memory. In addition, extracellular recordings from CA1 and dentate gyrus (DG) regions of the hippocampus in urethane anesthetized rats showed a significant impairment of LTP after 24‐ and 48‐h SD. Treatment of normal rats with nicotine for 24 or 48 h did not enhance spatial learning and memory or affect magnitude of LTP in the CA1 and DG regions. However, concurrent, acute treatment of rats with nicotine significantly attenuated SD‐induced impairment of learning and STM and prevented SD‐induced impairment of LTP in the CA1 and DG regions. These results show that acute nicotine treatment prevented the deleterious effect of sleep loss on cognitive abilities and synaptic plasticity. © 2010 Wiley‐Liss, Inc.     

Amyloid fibrils induce dysfunction of hippocampal glutamatergic silent synapses

Silent glutamatergic synapses lacking functional AMPA (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazoleproprionate) receptors exist in several brain regions including the hippocampus. Their involvement in the dysfunction of hippocampal glutamatergic transmission in the setting of Alzheimer's disease (AD) is unknown. This study demonstrated a decrease in the percentage of silent synapses in rats microinjected with amyloid fibrils (Aβ_1–40) into the hippocampal CA1. Also, pairing low‐frequency electric stimuli failed to induce activation of the hippocampal silent synapses in the modeled rats. Immunoblotting studies revealed a decreased expression of GluR1 subunits in the hippocampal CA1 synaptosomal preparation, indicating a potential reduction in the GluR1 subunits anchoring in postsynaptic density in the modeled rats. We also noted a decreased expression of phosphorylated cofilin, which regulates the function of actin cytoskeleton and receptor trafficking, and reduced expression of the scaffolding protein PSD95 in the hippocampal CA1 synaptosome in rats injected with Aβ_1–40. Taken together, this study illustrates dysfunction of hippocampal silent synapse in the rodent model of AD, which might result from the impairments of actin cytoskeleton and postsynaptic scaffolding proteins induced by amyloid fibrils.     

Hyper-Rigid Phasic Organization of Hippocampal Activity But Normal Spatial Properties of CA1 Place Cells in the Ts65Dn Mouse Model of Down Syndrome

Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations on the theta wave are thought to play a critical role in hippocampal function, the changes we observe agree with recent findings that organization of the hippocampal network is potentially of more relevance to its function than the spatial properties of place cells.SIGNIFICANCE STATEMENT Recent evidence has disrupted the view that spatial deficits are associated with place cell abnormalities. In these experiments, we record hippocampal place cells and local field potential from the Ts65Dn mouse model of Down syndrome, and find phenomenologically normal place cells, but profound changes in the association of place cells and gamma rhythms with theta rhythm, suggesting that the overall network state is critically important for hippocampal function. These findings also agree with evidence suggesting that excess inhibitory control is the cause of hippocampal dysfunction in Down syndrome. The findings also confirm new avenues for pharmacological treatment of Down syndrome.     

Place navigation in the Morris water task results in greater nuclear Arc mRNA expression in dorsal compared to ventral CA1

Previous work has shown that the dorsal hippocampus has greater activity than ventral regions during place navigation. Exposure to a novel context has also been found to increase hippocampal activation, possibly due to increased spatial demands. However, activation patterns in dorsal and ventral regions have not been investigated in the Morris water task (MWT), which remains the most popular assay of place memory in rodents. We measured activity in a large population of neurons across the CA1 dorsal–ventral axis by estimating nuclear Arc mRNA with stereologic systematic‐random sampling procedures following changes to goal location or spatial context in the MWT in rats. Following changes to goal location or spatial context in the MWT, we did not find an effect on Arc mRNA expression in CA1. However, Arc expression was greater in the dorsal compared to the ventral aspect of CA1 during task performance. Several views might account for these observed differences in dorsal–ventral Arc mRNA expression, including task parameters or the granularity of representation that differs along the dorsal–ventral hippocampal axis. Future work should determine the effects of task differences and required memory precision in relation to dorsal–ventral hippocampal neuronal activity.     

Circulating corticosterone alters the rate of neuropathological and behavioral changes induced by trimethyltin in rats.

When trimethyltin (TMT) is administered to rats, the plasma corticosterone concentration rises transiently 3 to 4 days later. We examined whether plasma corticosterone plays a causative role in the TMT-induced impairment of the hippocampus as assessed by pathological and behavioral tests. TMT-administered rats were supplementally treated with either adrenalectomy or metyrapone (twice daily for the first 7 days after TMT) in order to permanently deplete or transiently suppress circulating corticosterone. Loss of pyramidal cells in the CA1 and CA3 fields, mossy fiber sprouting, and impairment of spatial memory were observed after TMT intoxication. Adrenalectomy apparently aggravated both the hippocampal damage and the spatial memory impairment induced by TMT treatment. The TMT+metyrapone treatment groups exhibited a significant reduction in pyramidal cells in both the CA1 and the CA3 regions. However, the neuronal damage in CA1 was significantly different between the TMT and the TMT+metyrapone groups. Metyrapone significantly reduced the TMT-induced damage to pyramidal cells in CA1, but not CA3, and it also abolished mossy fiber sprouting. TMT-induced learning impairment and hyperactivity were alleviated by metyrapone treatment. It is thus concluded that both the high levels of corticosterone induced by TMT and the pathologically low levels of corticosterone induced by adrenalectomy will worsen the consequences of TMT.     

Effects of increasing CREB‐dependent transcription on the storage and recall processes in a hippocampal CA1 microcircuit

The involvement of the hippocampus in learning processes and major brain diseases makes it an ideal candidate to investigate possible ways to devise effective therapies for memory‐related pathologies like Alzheimer's Disease (AD). It has been previously reported that augmenting CREB activity increases the synaptic Long‐Term Potentiation (LTP) magnitude in CA1 pyramidal neurons and their intrinsic excitability in healthy rodents. It has also been suggested that hippocampal CREB signaling is likely to be down‐regulated during AD, possibly degrading memory functions. Therefore, the concept of CREB‐based memory enhancers, i.e. drugs that would boost memory by activation of CREB, has emerged. Here, using a model of a CA1 microcircuit, we investigate whether hippocampal CA1 pyramidal neuron properties altered by increasing CREB activity may contribute to improve memory storage and recall. With a set of patterns presented to a network, we find that the pattern recall quality under AD‐like conditions is significantly better when boosting CREB function with respect to control. The results are robust and consistent upon increasing the synaptic damage expected by AD progression, supporting the idea that the use of CREB‐based therapies could provide a new approach to treat AD. © 2013 Wiley Periodicals, Inc.     

Behavior‐driven arc expression is reduced in all ventral hippocampal subfields compared to CA1, CA3, and dentate gyrus in rat dorsal hippocampus

Anatomical connectivity and lesion studies reveal distinct functional heterogeneity along the dorsal–ventral axis of the hippocampus. The immediate early gene Arc is known to be involved in neural plasticity and memory and can be used as a marker for cell activity that occurs, for example, when hippocampal place cells fire. We report here, that Arc is expressed in a greater proportion of cells in dorsal CA1, CA3, and dentate gyrus (DG), following spatial behavioral experiences compared to ventral hippocampal subregions (dorsal CA1 = 33%; ventral CA1 = 13%; dorsal CA3 = 23%; ventral CA3 = 8%; and dorsal DG = 2.5%; ventral DG = 1.2%). The technique used here to obtain estimates of numbers of behavior‐driven cells across the dorsal–ventral axis, however, corresponds quite well with samples from available single unit recording studies. Several explanations for the two‐ to‐threefold reduction in spatial behavior‐driven cell activity in the ventral hippocampus can be offered. These include anatomical connectivity differences, differential gain of the self‐motion signals that appear to alter the scale of place fields and the proportion of active cells, and possibly variations in the neuronal responses to non‐spatial information within the hippocampus along its dorso‐ventral axis.     

Effect of brain‐derived neurotrophic factor haploinsufficiency on stress‐induced remodeling of hippocampal neurons

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity‐dependent manner, as a mediator of the stress‐induced dendritic remodeling. The analysis of Golgi‐impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF^±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF^± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF^± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. © 2010 Wiley‐Liss, Inc.     

Exploring the role of context-dependent hippocampal activity in spatial alternation behavior

In a continuous T-maze spatial alternation task, CA1 place cells fire differentially on the stem of the maze as rats are performing left- and right-turn trials (Wood et al. (2000) Neuron 27:623-633). This context-dependent hippocampal activity provides a potential mechanism by which animals could solve the alternation task, as it provides a cue that could prime the appropriate goal choice. The aim of this study was to examine the relationship between context-dependent hippocampal activity and spatial alternation behavior. We report that rats with complete lesions of the hippocampus learn and perform the spatial alternation task as well as controls if there is no delay between trials, suggesting that the observed context-dependent hippocampal activity does not mediate alternation behavior in this task. However lesioned rats are significantly impaired when delays of 2 or 10 s are interposed. Recording experiments reveal that context-dependent hippocampal activity occurs in both the delay and no-delay versions of the task, but that in the delay version it occurs during the delay period, and not on the stem of the maze. These data are consistent with a role for context-dependent hippocampal activity in delayed spatial alternation, but suggest that, according to specific task demands and memory load, the activity may be generated by different mechanisms and/or in different brain structures.     

Basal and learning task-related brain oxidative metabolism in cirrhotic rats

Hepatic encephalopathy is a neurological complication observed in patients with liver disease. Subjects with hepatic encephalopathy can develop memory alterations. In order to investigate brain oxidative metabolism in an animal model of chronic cirrhosis and its modification after spatial working memory task, we determined the neural metabolic activity of several brain limbic system regions by cytochrome oxidase (COx) histochemistry and assessed the spatial working memory in the Morris water maze of rats with cirrhosis by administration of thioacetamide. This COx histochemistry was done in cirrhotic and control rats under basal conditions and after the spatial working memory task. The histochemical results showed differences in basal COx activity between control and cirrhotic rats in hippocampal and thalamic regions. In cirrhotic rats basal COx activity was increased in the CA1 and CA3 areas of the hippocampus and reduced in the anterodorsal and anteroventral thalamic nuclei. We found impaired spatial working memory in animals with cirrhosis. These animals showed absence of metabolic activation of the CA3 hippocampal subfield and the lateral mammillary nucleus and disturbance of COx activity in the medial mammillary nucleus and the anteroventral thalamus. These findings suggest that cirrhotic rats show spatial working memory deficits that could be related to the alteration of metabolic activity of neural regions thought to be involved in the processing of spatial memories.     

Early dysregulation of hippocampal proteins in transgenic rats with Alzheimer's disease-linked mutations in amyloid precursor protein and presenilin 1

The response of the hippocampal proteome to expression of mutant proteins present in familial forms of Alzheimer's disease (AD) was studied using transgenic rats. These animals carry both the amyloid precursor protein Swedish and 717 mutation (APP(SW+717)) as well as the presenilin 1 Finnish mutation (PS1(FINN)). This transgenic rat model displays intracellular amyloid beta (Abeta) in neurons of the neocortex and the hippocampus (CA2 and CA3). The hippocampus was selected as it is one of the first brain regions affected in AD and is involved in the processing of short-term memory and spatial memory. Applying a proteomic approach, we demonstrate that the expression of APP(SW+717) and PS1(FINN) transgenes causes changes in expression of hippocampal proteins, some of which have been previously linked to learning and memory formation. The protein alterations documented here occur in the absence of plaque formation and prior to the onset of cognitive deficits later observed in these transgenic rats. This indicates that molecular changes take place in the hippocampal neurons in response to expression of mutant proteins APP(SW+717) and PS1(FINN), which precede the occurrence of overt extracellular accumulation of extracellular amyloid. The implications of these findings on our understanding of the early stages of AD are discussed.