Increased hippocampal neurogenesis in the progressive stage of Alzheimer's disease phenotype in an APP/PS1 double transgenic mouse model

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile β‐amyloid (Aβ) plaques and cognitive decline. Neurogenesis in the adult hippocampus is implicated in regulating learning and memory, and is increased in human postmortem brain of AD patients. However, little is currently known about the changes of hippocampal neurogenesis in the progression of AD. As brain tissues from patients during the progression of AD are generally not available, an amyloid precursor protein (APP)/presenilin1 (PS1) double transgenic mouse model of AD was studied. Bromodeoxyuridine (BrdU) labeling supported by doublecortin staining was used to detect proliferating hippocampal cells in the mice. Compared with age‐matched wild‐type controls, 9‐month‐old transgenic mice with memory impairment and numerous brain Aβ deposits showed increased numbers of proliferating hippocampal cells. However, 3‐month‐old transgenic mice with normal memory and subtle brain Aβ deposits showed normal hippocampal proliferation. Double immunofluorescent labeling with BrdU and either NeuN or glial fibrillary acidic protein was conducted in mice at 10 months (28 days after the last BrdU injection) to determine the differentiation of proliferating cells. The number of hippocampal BrdU‐positive cells and BrdU‐positive cells differentiating into neurons (neurogenesis) in 10‐month‐old mice was greater in transgenic mice compared with age‐matched controls, but the ratio of hippocampal BrdU‐positive cells differentiating into neurons and astroglia was comparable. These results suggest hippocampal neurogenesis may increase during the progression of AD. Targeting this change in neurogenesis and understanding the underlying mechanism could lead to the development of a new treatment to control the progression of AD. © 2009 Wiley‐Liss, Inc.     

Onset of hippocampus‐dependent memory impairments in 5XFAD transgenic mouse model of Alzheimer's disease

The 5XFAD mice are an early‐onset transgenic model of Alzheimer's disease (AD) in which amyloid plaques are first observed between two and four months of age in the cortical layer five and in the subiculum of the hippocampal formation. Although cognitive alterations have been described in these mice, there are no studies that focused on the onset of hippocampus‐dependent memory deficits, which are a hallmark of the prodromal stage of AD. To identify when the first learning and memory impairments appear, 5XFAD mice of two, four, and six months of age were compared with their respective wild‐type littermates using the olfactory tubing maze, which is a very sensitive hippocampal‐dependent task. Deficits in learning and memory started at four months with a substantial increase at six months of age while no olfactory impairments were observed. The volumetric study using magnetic resonance imaging of the whole brain and specific areas (olfactory bulb, striatum, and hippocampus) did not reveal neuro‐anatomical difference. Slight memory deficits appeared at 4 months of age in correlation with an increased astrogliosis and amyloid plaque formation. This early impairment in learning and memory related to the hippocampal dysfunction is particularly suited to assess preclinical therapeutic strategies aiming to delay or suppress the onset of AD. © 2014 Wiley Periodicals, Inc.     

Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice

Evidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimer's disease (AD). Its antioxidant, anti‐inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The underlying mechanism, however, is complex and is still being explored. In this study, we used the APPswe/PS1dE9 double transgenic mice, an AD model, to investigate the effects and mechanisms of curcumin in the prevention and treatment of AD. The water maze test indicated that curcumin can improve spatial learning and memory ability in mice. Immunohistochemical staining and Western blot analysis were used to test major proteins in β‐amyloid aggregation, β‐amyloid production, and β‐amyloid clearance. Data showed that, 3 months after administration, curcumin treatment reduced Aβ₄₀, Aβ₄₂, and aggregation of Aβ‐derived diffusible ligands in the mouse hippocampal CA1 area; reduced the expression of the γ‐secretase component presenilin‐2; and increased the expression of β‐amyloid‐degrading enzymes, including insulin‐degrading enzymes and neprilysin. This evidence suggests that curcumin, as a potential AD therapeutic method, can reduce β‐amyloid pathological aggregation, possibly through mechanisms that prevent its production by inhibiting presenilin‐2 and/or by accelerating its clearance by increasing degrading enzymes such as insulin‐degrading enzyme and neprilysin. © 2013 Wiley Periodicals, Inc.     

Genetic reductions of β‐site amyloid precursor protein‐cleaving enzyme 1 and amyloid‐β ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer’s disease model mice

Although transgenic mouse models of Alzheimer’s disease (AD) recapitulate amyloid‐β (Aβ)‐related pathologies and cognitive impairments, previous studies have mainly evaluated their hippocampus‐dependent memory dysfunctions using behavioral tasks such as the water maze and fear conditioning. However, multiple memory systems become impaired in AD as the disease progresses and it is important to test whether other forms of memory are affected in AD models. This study was designed to use conditioned taste aversion (CTA) and contextual fear conditioning paradigms to compare the phenotypes of hippocampus‐independent and ‐dependent memory functions, respectively, in 5XFAD amyloid precursor protein/presenilin‐1 transgenic mice that harbor five familial AD mutations. Although both types of memory were significantly impaired in 5XFAD mice, the onset of CTA memory deficits (～9 months of age) was delayed compared with that of contextual memory deficits (～6 months of age). Furthermore, 5XFAD mice that were genetically engineered to have reduced levels of β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) (BACE1^+/?·5XFAD) exhibited improved CTA memory, which was equivalent to the performance of wild‐type controls. Importantly, elevated levels of cerebral β‐secretase‐cleaved C‐terminal fragment (C99) and Aβ peptides in 5XFAD mice were significantly reduced in BACE1^+/?·5XFAD mice. Furthermore, Aβ deposition in the insular cortex and basolateral amygdala, two brain regions that are critically involved in CTA performance, was also reduced in BACE1^+/?·5XFAD compared with 5XFAD mice. Our findings indicate that the CTA paradigm is useful for evaluating a hippocampus‐independent form of memory defect in AD model mice, which is sensitive to rescue by partial reductions of the β‐secretase BACE1 and consequently of cerebral Aβ.     

Essential role of tau phosphorylation in adult hippocampal neurogenesis

An increased hippocampal neurogenesis has been observed in Alzheimer disease (AD), the most common neurodegenerative disorder characterized with accumulation of β‐amyloid (Aβ) and hyperphosphorylated tau (p‐tau). Studies in transgenic mouse models suggest that the amyloidosis suppresses adult neurogenesis. Although emerging evidence links tau to neurodevelopment, the direct data regarding tau phosphorylation in adult neurogenesis is missing. Here, we found that the immature neurons, identified by doublecortin (DCX) and neurogenic differentiation factor (neuroD), were only immunoreactive to p‐tau but not to the non‐p‐tau in adult rat brain and human patients with AD, and the p‐tau was coexpressed temporally and spatially with DCX and neuroD in the hippocampal dentate gyrus (DG) of the rat brains during postnatal development. A correlative increase of immature neuron markers and tau phosphorylation was induced in rat hippocampal DG by upregulating glycogen synthase kinase‐3 (GSK‐3), a crucial tau kinase, and the increased neurogenesis was due to an enhanced proliferation but not survival or differentiation of the newborn neurons. The hippocampal neurogenesis was severely impaired in tau knockout mice and activation of GSK‐3 in these mice did not rescue the deficits. These results reveal an essential role of tau phosphorylation in adult hippocampal neurogenesis. It suggests that spatial/temporal manipulation of tau phosphorylation may be compensatory for the neuron loss in neurological disorders, including AD. © 2009 Wiley‐Liss, Inc.     

Microsomal prostaglandin E synthase‐1 is induced in alzheimer's disease and its deletion mitigates alzheimer's disease‐like pathology in a mouse model

Epidemiological studies have suggested that long‐term use of nonsteroidal anti‐inflammatory drugs that inhibit cyclooxygenase (COX) activity can moderate the onset or progression of Alzheimer's disease (AD). Thus it has been suggested that prostaglandin E₂ (PGE₂), a major end‐product of COX, may play a pathogenic role in AD, but the involvement of PGE synthase (PGES), a terminal enzyme downstream from COX, has not been fully elucidated. Here we found that, among three PGES enzymes, only microsomal PGES‐1 (mPGES‐1) is induced, and its expression is associated with β‐amyloid (Aβ) plaques in the cerebral cortex in human AD patients and in Tg2576 mice, a transgenic AD mouse model. Furthermore, to investigate whether mPGES‐1 contributes to AD‐like pathology, we bred mPGES‐1‐deficient mice with Tg2576 mice. We found that mPGES‐1 deletion reduced the accumulation of microglia around senile plaques and attenuated learning impairments in Tg2576 mice. These results indicated that mPGES‐1 is induced in the AD brain and thus plays a role in AD pathology. Blockage of mPGES‐1 could form the basis for a novel therapeutic strategy for patients with AD. Inc. © 2013 Wiley Periodicals, Inc.     

Abnormal processing of tau in the brain of aged TgCRND8 mice

Amyloid plaques and neurofibrillary tangles are the main histopathological hallmarks of Alzheimer's disease (AD). In the neocortex and hippocampus of aged TgCRND8 mice, tau is hyperphosphorylated at different sites recognized by PHF-1, AT100, AT8 and CP13 antibodies. Phospho-SAPK/JNK levels were increased in the tg mouse brain, where activated SAPK/JNK co-localizes with PHF-1-positive cells. Phosphorylated tau-positive cells showed Bielschowsky- and Thioflavine S-positive intraneuronal deposits. PHF-1 and nitrotyrosine immunoreactivity merged within neurons surrounding amyloid deposits in cortical and hippocampal areas and immunoprecipitation studies confirmed that tau is nitrosylated. Our findings, demonstrating the presence of hyperphosphorylated and nitrosylated tau protein as well as of insoluble aggregates after the onset of amyloid deposition in the TgCRND8 mouse brain, indicate that the abnormal processing of tau may occur subsequently to cerebral amyloidosis and that activation of SAPK/JNK and induction of nitrosative stress are the more likely connecting factors between amyloidosis and tauopathy in AD.     

Hyperforin prevents beta-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-beta-deposits

The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid beta-peptide (Abeta). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Abeta-induced spatial memory impairments and on Abeta neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Abeta-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Abeta oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Abeta aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.     

Hypoxia‐Induced Loss of Synaptic Transmission Is Exacerbated in Hippocampal Slices of Transgenic Mice Expressing C‐Terminal Fragments of Alzheimer Amyloid Precursor Protein

To investigate the possible involvement of β‐amyloid (Aβ) in disrupting neuronal function during ischemia, we examined whether overexpression of C‐terminal fragments of β‐amyloid precursor protein (β‐APP) in transgenic (Tg) mice is capable of altering the capacity of hippocampus slices to recover synaptic transmission after transient hypoxic episodes. Recovery of synaptic transmission was monitored in area CA₁ of perfused hippocampal slices prepared from both control and Tg mice. The results obtained indicate that hippocampal slices prepared from Tg mice exhibited a much lower level of recovery in synaptic transmission following reoxygenation. This reduction in the capacity of Tg slices to recover from hypoxia‐induced impairment of synaptic transmission in the hippocampus does not appear to be related to pre‐existing alterations in either functional or biochemical properties of glutamate receptors in Tg mice. The present results provide the first experimental evidence that overexpression of the C‐terminal fragment of APP exacerbates functional damage of hippocampal neurons after hypoxic episodes. Hippocampus 1999;9:201–205. © 1999 Wiley‐Liss, Inc.     

Serotonin fibre sprouting and increase in serotonin transporter immunoreactivity in the CA1 area of hippocampus in a triple transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease that deteriorates cognitive functions and associated brain regions such as the hippocampus, being the primary cause of dementia. Serotonin (5‐HT) is widely present in the hippocampus, being an important neurotransmitter involved in learning and memory. Although recent evidence suggests alterations in 5‐HT neurotransmission in AD, it is not clear how hippocampal 5‐HT innervation is modified. Here, we studied hippocampal 5‐HT innervation by analysing: (i) the expression, density and distribution of 5‐HT transporter (SERT)‐immunoreactive fibres; (ii) the specific morphological characteristics of serotonergic fibres and their relation to amyloid plaques; and (iii) the total number of 5‐HT neurons within the raphe nuclei in triple transgenic mouse model of AD. We used quantitative light microscopy immunohistochemistry comparing transgenic and non‐transgenic animals of different ages (3, 6, 9, 12 and 18 months). The transgenic animals showed a significant increase in SERT fibres in the hippocampus in a subfield‐, strata‐ and age‐specific manner. The increase in SERT fibres was specific to the CA1 stratum lacunosum‐moleculare. An increase in SERT fibres in transgenic animals was observed at 3 months (by 61%) and at 18 months (by 74%). No changes, however, were found in the total number of raphe 5‐HT neurons at any age. Our results indicate that triple transgenic mice display changes in the expression of SERT and increased SERT fibres sprouting, which may account for imbalanced serotonergic neurotransmission associated with (or linked to) AD cognitive impairment.     

NMDA receptor–dependent signaling pathways that underlie amyloid β‐protein disruption of LTP in the hippocampus

Alzheimer's disease (AD), the most common neurodegenerative disease in the elderly population, is characterized by the hippocampal deposition of fibrils formed by amyloid β‐protein (Aβ), a 40‐ to 42‐amino‐acid peptide. The folding of Aβ into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is believed to mediate the key pathologic event in AD. The hippocampus is especially susceptible in AD and early degenerative symptoms include significant deficits in the performance of hippocampal‐dependent cognitive abilities such as spatial learning and memory. Transgenic mouse models of AD that express C‐terminal segments or mutant variants of amyloid precursor protein, the protein from which Aβ is derived, exhibit age‐dependent spatial memory impairment and attenuated long‐term potentiation (LTP) in the hippocampal CA1 and dentate gyrus (DG) regions. Recent experimental evidence suggests that Aβ disturbs N‐methyl‐D ‐aspartic acid (NMDA) receptor–dependent LTP induction in the CA1 and DG both in vivo and in vitro. Furthermore, these studies suggest that Aβ specifically interferes with several major signaling pathways downstream of the NMDA receptor, including the Ca²⁺‐dependent protein phosphatase calcineurin, Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII), protein phosphatase 1, and cAMP response element–binding protein (CREB). The influence of Aβ on each of these downstream effectors of the NMDA receptor is reviewed in this article. Additionally, other mechanisms of LTP modulation, such as Aβ attenuation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor currents, are briefly discussed. © 2009 Wiley‐Liss, Inc.     

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.     

Sex Steroid Levels and AD‐Like Pathology in 3xTgAD Mice

Decreases in testosterone and 17β‐oestradiol (E₂) are associated with an increased risk for Alzheimer's disease (AD), which has been attributed to an increase in β‐amyloid and tau pathological lesions. Although recent studies have used transgenic animal models to test the effects of sex steroid manipulations on AD‐like pathology, almost none have systematically characterised the associations between AD lesions and sex steroid levels in the blood or brain in any mutant model. The present study evaluated age‐related changes in testosterone and E₂ concentrations, as well as androgen receptor (AR) and oestrogen receptor (ER) α and β expression, in brain regions displaying AD pathology in intact male and female 3xTgAD and nontransgenic (ntg) mice. We report for the first time that circulating and brain testosterone levels significantly increase in male 3xTgAD mice with age, but without changes in AR‐immunoreactive (IR) cell number in the hippocampal CA1 or medial amygdala. The age‐related increase in hippocampal testosterone levels correlated positively with increases in the conformational tau isoform, Alz50. These data suggest that the over‐expression of human tau up‐regulate the hypothalamic‐pituitary‐gonadal axis in these mice. Although circulating and brain E₂ levels remained stable with age in both male and female 3xTgAD and ntg mice, ER‐IR cell number in the hippocampus and medial amygdala decreased with age in female transgenic mice. Furthermore, E₂ levels were significantly higher in the hippocampus than in serum, suggesting local production of E₂. Although triple transgenic mice mimic AD‐like pathology, they do not fully replicate changes in human sex steroid levels, and may not be the best model for studying the effects of sex steroids on AD lesions.     

Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease

Alzheimer's disease (AD) is the most common progressive dementia and is pathologically characterized by brain deposition of amyloid‐β (Aβ) peptide as senile plaques. Inflammatory and immune response pathways are chronically activated in AD patient brains at low levels, and likely play a role in disease progression. Like microglia, activated astrocytes produce numerous acute‐phase reactants and proinflammatory molecules in the AD brain. One such molecule, S100B, is highly expressed by reactive astrocytes in close vicinity of β‐amyloid deposits. We have previously shown that augmented and prolonged activation of astrocytes has a detrimental impact on neuronal survival. Furthermore, we have implicated astrocyte‐derived S100B as a candidate molecule responsible for this deleterious effect. To evaluate a putative relationship between S100B and AD pathogenesis, we crossed transgenic mice overexpressing human S100B (TghuS100B mice) with the Tg2576 mouse model of AD, and examined AD‐like pathology. Brain parenchymal and cerebral vascular β‐amyloid deposits and Aβ levels were increased in bigenic Tg2576‐huS100B mice. These effects were associated with increased cleavage of the β‐C‐terminal fragment of amyloid precursor protein (APP), elevation of the N‐terminal APP cleavage product (soluble APPβ), and activation of β‐site APP cleaving enzyme 1. In addition, double transgenic mice showed augmented reactive astrocytosis and microgliosis, high levels of S100 expression, and increased levels of proinflammatory cytokines as early as 7–9 months of age. These results provide evidence that (over)‐expression of S100B acts to accelerate AD‐like pathology, and suggest that inhibiting astrocytic activation by blocking S100B biosynthesis may be a promising therapeutic strategy to delay AD progression. © 2009 Wiley‐Liss, Inc.     

γ‐Secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ

Deposition of β ‐amyloid (Aβ) peptides, cleavage products of β‐amyloid precursor protein (APP) by β‐secretase‐1 (BACE1) and γ‐secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ‐Secretase inhibition is a therapeutical anti‐Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti‐Aβ efficacy. The present study compared active γ‐secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [³H]‐L‐685,458, a radiolabeled high‐affinity γ‐secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post‐mortem delays. The CP in post‐mortem samples exhibited exceptionally high [³H]‐L‐685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin‐1 immunoreactivity, and β‐site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ‐secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non‐neuronal contributor to CSF Aβ, probably at reduced levels in AD.     

In vivo labelling of hippocampal β‐amyloid in triple‐transgenic mice with a fluorescent acetylcholinesterase inhibitor released from nanoparticles

The drastic loss of cholinergic projection neurons in the basal forebrain is a hallmark of Alzheimer’s disease (AD), and drugs most frequently applied for the treatment of dementia include inhibitors of the acetylcholine‐degrading enzyme acetylcholinesterase (AChE). This protein is known to act as a ligand of β‐amyloid (Aβ) in senile plaques, a further neuropathological sign of AD. Recently, we have shown that the fluorescent, heterodimeric AChE inhibitor PE154 allows for the histochemical staining of cortical Aβ plaques in triple‐transgenic (TTG) mice with age‐dependent β‐amyloidosis and tau hyperphosphorylation, an established animal model for aspects of AD. In the present study, we have primarily demonstrated the targeting of Aβ‐immunopositive plaques with PE154 in vivo for 4 h up to 1 week after injection into the hippocampi of 13–20‐month‐old TTG mice. Numerous plaques, double‐stained for PE154 and Aβ‐immunoreactivity, were revealed by confocal laser‐scanning microscopy. Additionally, PE154 targeted hippocampal Aβ deposits in aged TTG mice after injection of carboxylated polyglycidylmethacrylate nanoparticles delivering the fluorescent marker in vivo. Furthermore, biodegradable core‐shell polystyrene/polybutylcyanoacrylate nanoparticles were found to be suitable, alternative vehicles for PE154 as a useful in vivo label of Aβ. Moreover, we were able to demonstrate that PE154 targeted Aβ, but neither phospho‐tau nor reactive astrocytes surrounding the plaques. In conclusion, nanoparticles appear as versatile carriers of AChE inhibitors and other promising drugs for the treatment of AD.     

Neuronal and glial alterations,increased anxiety,and cognitive impairment before hippocampal amyloid deposition in PDAPP mice,model of Alzheimer's disease

In the context of Alzheimer's disease (AD), hippocampal alterations have been well described in advanced stages of the pathology, when amyloid deposition, inflammation and glial activation occur, but less attention has been directed to studying early brain and behavioral changes. Using an animal model of AD, the transgenic PDAPP‐J20 mouse at 5 months of age, when no amyloid plaques are present and low cerebral levels of amyloid peptides are detectable, we found structural, morphological, and cellular alterations in the hippocampus. Young transgenic mice showed a reduced hippocampal volume with less number of pyramidal and granular neurons, which additionally exhibited cell atrophy. The neurogenic capability in this zone, measured as DCX+ cells, was strongly diminished and associated to alterations in cell maturity. A decrease in presynaptic synaptophysin optical density was detected in mossy fibers reaching CA3 subfield but not in Golgi stained‐ CA1 dendritic spine density. Employing confocal microscopy and accurate stereological tools we also found a reduction in the number of GFAP+ cells, along with decreased astrocyte complexity, suggesting a potential detriment of neural support. According with untimely neuroglial alterations, young PDAPP mice failed in the novel location recognition test, that depends on hippocampal function. Moreover, multivariate statistical analysis of the behavioral outcome in the open‐field test evidenced an elevated anxiety score in Tg mice compared with age‐matched control mice. In line with this, the transgenic group showed a higher number of c‐Fos+ nuclei in central and basolateral amygdala, a result that supports the early involvement of the emotionality factor in AD pathology. Applying an integrative approach, this work focuses on early structural, morphological and functional changes and provides new and compelling evidence of behavioral alterations that precede manifest AD. © 2013 Wiley Periodicals, Inc.     

Fluoxetine delays the cognitive function decline and synaptic changes in a transgenic mouse model of early Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline. Previous studies have reported that the syndrome of AD begins with subtle alterations in hippocampal synapses prior to frank neuronal degeneration. It has recently been reported that fluoxetine (FLX) shows positive effects on AD patients who have depression and anxiety. However, it is unclear whether FLX can affect the pathogenesis of AD mice in the early stage of AD. To address this question, 8-month-old male APP/PS1 double-transgenic AD mice were administered a 10-week course of FLX (10 mg/kg/day) injections. Then, spatial learning and memory were evaluated using a Morris water maze test. Immunohistological staining and an unbiased stereological method were used to estimate the total number of dendritic spine synapses in the hippocampus. We found that FLX significantly shortened the mean escape latencies of the 10-month-old mice; reduced the elevated levels of soluble Aβ40, Aβ42, and amyloid plaques in the hippocampus; and prevented the decrease in dendritic spine synapses and in postsynaptic protein PSD-95 density in the dentate gyrus, CA1/2 and CA3 regions of the hippocampus. Our results indicate that reversing synaptic impairment might be considered a promising therapeutic approach for alleviating the cognitive deficits associated with early AD. Moreover, our results suggest that FLX may be a safe and effective drug for delaying the progress of AD, which might provide a starting point for further research into new preventative measures and treatments for AD.     

Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model

Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer‐like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble β‐amyloid (Aβ) which could be significantly inhibited by fluoxetine (FLX) via activating serotonin 5‐HT₂ receptors. FLX could also protect hippocampal neurons against astrocyte‐induced neuronal damage in vitro. In the same APP/PS1 mice, FLX inhibited activation of astrocytes, lowered Aβ products, ameliorated neurotoxicity, and improved behavioral performance. These findings may provide a basis for the clinical application of FLX in patients, and may also lay the groundwork for exploration of other novel astrocyte‐based therapies of AD. GLIA 2016;64:240–254