Interval timing is disrupted in female 5xFAD mice: An indication of altered memory processes

Temporal information processing in the seconds-to-minutes range is disrupted in patients with Alzheimer's disease (AD). In this study, we investigated the timing behavior of the 5xFAD mouse model of AD in the peak interval (PI) procedure. Nine-month-old female mice were trained with sucrose solution reinforcement for their first response after a fixed-interval (FI) and tested in the inter-mixed non-reinforced PI trials that lasted longer than FI. Timing performance indices were estimated from steady-state timed anticipatory nose-poking responses in the PI trials. We found that the time of maximal reward expectancy (peak time) of the 5xFAD mice was significantly earlier than that of the wild-type (WT) controls with no differences in other indices of timing performance. These behavioral differences corroborate the findings of previous studies on the disruption of temporal associative memory abilities of 5xFAD mice and can be accounted for by the scalar timing theory based on altered long-term memory consolidation of temporal information in the 5xFAD mice. This is the first study to directly show an interval timing phenotype in a genetic mouse model of AD.     

Mildronate improves cognition and reduces amyloid‐β pathology in transgenic Alzheimer's disease mice

Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine‐induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP_SweDI). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD‐related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid‐β deposition in the hippocampus, increased expression of the microglia marker Iba‐1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP‐43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid‐β pathology in a mouse model of AD and its possible therapeutic utility as a disease‐modifying drug in AD patients. © 2013 Wiley Periodicals, Inc.     

Age-dependent time course of cerebral brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 in APP23 transgenic mice

Neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), have repeatedly been shown to be involved in the pathophysiology of Alzheimer's disease (AD). Recent studies have claimed that these neurotrophic factors are important tools for therapeutic intervention in neurodegenerative diseases. So far, little is known about the age- and disease-modulated time course of cerebral neurotrophins. Therefore, we have studied protein concentrations of BDNF, NGF, and NT-3 in different brain areas and sciatic nerve, a neurotrophin-transporting peripheral nerve, in a well-characterized AD model of amyloid precursor protein-overexpressing rodents (APP23 mice) at the ages of 5.0, 10.5, and 20.0 months. In APP23 mice, there was a significant increase of BDNF and NGF in the frontal and occipital cortices (for BDNF also in the striatum) of old 20.0-month-old mice (with respect to median values up to 8.2-fold), which was highly correlated with amyloid concentrations of these brain areas. Median values of NGF and NT-3 showed up to a 6.0-fold age-dependent increase in the septum that was not detectable in APP23 mice. Hippocampus, olfactory bulb, and cerebellum (except NT-3) did not show substantial age- or genotype-related regulation of neurotrophins. In the sciatic nerve, BDNF and NGF levels are increased in5-month-old APP23 mice and decrease with age to control levels. In conclusion, APP23 mice show a genotype-dependent increase of cortical BDNF and NGF that is highly correlated with amyloid concentrations and may reflect an amyloid-related glia-derived neurotrophin secretion or an altered axonal transport of these neurotrophic factors.     

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice

Alzheimer's disease (AD) is characterized by progressive decline of cognition and associated neuropsychiatric signs including weight loss, anxiety, depression, agitation, and aggression, which is particularly pronounced in the female gender. Previously, we have shown that a novel ionic co-crystal of lithium salicylate proline (LISPRO) is an improved lithium formulation compared to the carbonate or salicylate form of lithium in terms of safety and efficacy in reducing AD pathology in Alzheimer's mice. The current study is designed to compare the prophylactic effects of LISPRO, lithium carbonate (LC), and lithium salicylate (LS) on cognitive and noncognitive impairments in female transgenic APPswe/PS1dE9 AD mice. Female APPswe/PS1dE9 mice at 4 months of age were orally treated with low-dose LISPRO, LS, or LC for 9 months at 2.25 mmol lithium/kg/day followed by determination of body weight, growth of internal organs, and cognitive and noncognitive behavior. No significant differences in body or internal organ weight, anxiety or locomotor activity were found between lithium treated and untreated APPswe/PS1dE9 cohorts. LISPRO, LC, and LS prevented spatial cognitive decline, as determined by Morris water maze and depression as determined by tail suspension test. In addition, LISPRO treatment was superior in preventing associative memory decline determined by contextual fear conditioning and reducing irritability determined by touch escape test in comparison with LC and LS. In conclusion, low-dose LISPRO, LC, and LS treatment prevent spatial cognitive decline and depression-like behavior, while LISPRO prevented hippocampal-dependent associative memory decline and irritability in APPswe/PS1dE9 mice.     

Enhanced accumulation of phosphorylated alpha-synuclein in double transgenic mice expressing mutant beta-amyloid precursor protein and presenilin-1

A recent report showed that the accumulation of alpha-synuclein (alpha-syn) was detected in the brains of one-third of Alzheimer's disease and Down syndrome patients. However, the relationship between amyloid-beta protein (Abeta) and alpha-syn remains unclear. We analyzed the relation between the mutation of presenilin-1 (PS-1) and the pathological features of beta-amyloidosis and alpha-synucleinopathy. We generated doubly transgenic mice overexpressing mutant beta-amyloid precursor protein (betaAPP; Tg2576) and mutant PS-1 (PS1L286Vtg; line 198) and analyzed 19 double Tg betaAPP(+)/PS(+) mice at 5-23 months (young to old), 23 age-matched single Tg betaAPP(+)/PS(-) mice, and 11 non-Tg littermates. Immunohistochemical comparison was performed in these three groups by counting the area and the number of alpha-syn- or phosphorylated alpha-syn (palpha-syn)-positive dystrophic neurites per plaque (ASPDN, pASPDN). The acceleration of Abeta pathology was found with earlier onset and exaggerated numbers in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains. The accumulation of ASPDN and pASPDN was also accelerated in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains, especially in pASPDN. The number and area of alpha-syn and palpha-syn, and the ratio of palpha-syn positive neurites were significantly higher in double Tg betaAPP(+)/PS(+) than in single Tg betaAPP(+)/PS(-) mouse brains in middle-aged and old groups. Additional overexpression of mutant PS-1 accelerated Abeta-induced alpha-synucleinopathy and further facilitated the phosphorylation of alpha-syn, suggesting a direct association between mutant PS-1 and phosphorylation of alpha-syn.     

Synaptic transmission and synchronous activity is disrupted in hippocampal slices taken from aged TAS10 mice

Synaptic transmission was studied in hippocampal slices from aged (12-14 months of age) TAS10 mice overexpressing the human form of the amyloid precursor protein harboring the Swedish mutation. A significant deficit in the input-output relationship of glutamatergic synapses in the CA3-CA1 Schaffer collateral pathway was observed, while synaptic transmission in the medial perforant pathway of the dentate gyrus was comparatively preserved. Despite this deficit, relative levels of short- and long-term synaptic plasticity in the CA1 region were similar to those observed in wildtype slices. Specifically, paired pulse facilitation, frequency facilitation (at frequencies of 1, 5, and 10 Hz), and long-term potentiation induced by a theta burst stimulation paradigm were all normal in the CA3-CA1 synapses of TAS10 hippocampal slices. However, synchronized network activity induced by bath application of 4-aminopyridine (4-AP) was compromised. Thus, the frequency of synchronous events induced by 100 microM 4-AP was significantly lower in TAS10 hippocampal slices (inter-event interval: WT, 2.4+/-0.6 s; TAS10, 6.9+/-1.7 s). To study gamma-aminobutyric acid (GABA)ergic synaptic transmission NBQX (20 microM) and D-AP5 (50 microM) were added in order to isolate bicuculline-sensitive GABA-mediated synchronous network activity. The GABAergic network activity was not significantly different from wildtype in terms of frequency. This study suggests that the deficit in glutamatergic synaptic transmission observed in the TAS10 hippocampal slices, may be coupled with alterations in synchronous network activity, which in turn would lead to deficient information processing.     

Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice

Genetic murine models play an important role in the study of human neurological disorders by providing accurate and experimentally accessible systems to study pathogenesis and to test potential therapeutic treatments. One of the most widely employed models of Huntington's disease (HD) is the R6/2 transgenic mouse. To characterize this model further, we have performed behavioral and neuropathological analyses that provide a foundation for the use of R6/2 mice in preclinical therapeutic trials. Behavioral analyses of the R6/2 mouse reveal age-related impairments in dystonic movements, motor performance, grip strength, and body weight that progressively worsen until death. Significant neuropathological sequela, identified as increasing marked reductions in brain weight, are present from 30 days, whereas decreased brain volume is present from 60 days and decreased neostriatal volume and striatal neuron area, with a concomitant reduction in striatal neuron number, are present at 90 days of age. Huntingtin-positive aggregates are present at postnatal day 1 and increase in number and size with age. Our findings suggest that the R6/2 HD model exhibits a progressive HD-like behavioral and neuropathological phenotype that more closely corresponds to human HD than previously believed, providing further assurance that the R6/2 mouse is an appropriate model for testing potential therapies for HD.     

Olfactory dysfunction in the APP/PS1 transgenic mouse model of Alzheimer's disease: Morphological evaluations from the nose to the brain

Olfactory dysfunction is among the signs of Alzheimer's disease (AD) and cognitive impairment. It has been demonstrated Aβ was associated with olfactory impairment observed in both transgenic mice and in AD patients. In this study, we evaluated amyloid deposition in the olfactory circuit of APP/PS1 transgenic mouse model of AD, which showed olfactory dysfunction in olfactory behavior tests. We found amyloid depositions were widely distributed in the whole olfactory circuit. Moreover, we think these amyloid depositions contribute to neuronal atrophy, dendritic abnormalities, synapse loss and axonal degeneration. Therefore, there was a correlation between olfactory deficits and amyloid deposition. Our findings provide initial insights into the pathological basis of AD‐related olfactory dysfunction.     

Synthetic PPAR Agonist DTMB Alleviates Alzheimer’s Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice

Abnormal productions of amyloid beta (Aβ) plaque and chronic neuroinflammation are commonly observed in the brain of patients with Alzheimer’s disease, and both of which induce neuronal cell death, loss of memory, and cognitive dysfunction. However, many of the drugs targeting the production of Aβ peptides have been unsuccessful in treating Alzheimer’s disease. In this study, we identified synthetic novel peroxisome proliferator-activating receptor (PPAR) agonist, DTMB, which can ameliorate the chronic inflammation and Aβ pathological progression of Alzheimer’s disease. We discovered that DTMB attenuated the proinflammatory cytokine production of microglia by reducing the protein level of NF-κB. DTMB also improved the learning and memory defects and reduced the amount of Aβ plaque in the brain of 5xFAD mice. This reduction in Aβ pathology was attributed to the changes in gliosis and chronic inflammation level. Additionally, bulk RNA-sequencing showed that genes related to inflammation and cognitive function were changed in the hippocampus and cortex of DTMB-treated mice. Our findings demonstrate that DTMB has the potential to be a novel therapeutic agent for Alzheimer’s disease.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01275-y.     

Mechanism of demyelination in DM20 transgenic mice involves increased fatty acylation

Transgenic mice (ND4) containing 70 copies of the transgene encoding DM20 were clinically normal up to 3 months of age, spontaneously demyelinated thereafter and died in 8–10 months. Whereas the myelin fraction from normal mice increased in amount from 1-4 months as expected, the corresponding fraction in ND4 mice remained constant over this period. In order to study the mechanism by which decreased myelin synthesis was manifest in the ND4 mouse, we investigated the amounts of proteolipids at various ages. The amount of proteolipid protein (PLP) was greatly decreased after 1–2 months in the ND4 mice. Although the message for DM20 was increased (transgene mRNA), very little DM20 was found in myelin at 1 month. It subsequently increased so that at 3–4 months the amount of DM20 in myelin isolated from transgenic animals was much higher than in normal mice. Characterization of the DM20 and PLP at 1 month of age showed that the amount of fatty acid (stearate and palmitate) was increased and the N-terminal glycine was methylated. These data suggested that high copy numbers of the cDNA for DM20 affected post translational events which we postulate affected the proper insertion of both DM20 and PLP in the myelin bilayer. J. Neurosci. Res. 53:143–152, 1998. © 1998 Wiley-Liss, Inc.     

The neuroprotective effect of deep brain stimulation at nucleus basalis of Meynert in transgenic mice with Alzheimer's disease

Background

Alzheimer's disease (AD) is the most common type of dementia and mainly treated by drugs, while the therapeutic outcomes are very limited. This study aimed to determine the optimized parameters of deep brain stimulation (DBS) which was applied to the treatment of AD and propose the involved mechanisms.

Effects of α5 GABAA receptor modulation on social interaction,memory, and neuroinflammation in a mouse model of Alzheimer's disease

AimsGABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer''s disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABA_A receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation.MethodsAfter 10‐day treatment with PAM, NAM, or solvent, 6‐month‐old transgenic and non‐transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL‐1β, IL‐6, TNF‐α, GFAP, and IBA‐1 were determined in hippocampus and prefrontal cortex by qPCR.ResultsPAM treatment impaired spatial learning in transgenic females compared to solvent‐treated transgenic females, and social recognition in transgenic and non‐transgenic males. NAM treatment declined social interaction in transgenic and non‐transgenic males, while had beneficial effect on cognitive flexibility in non‐transgenic males compared to solvent‐treated non‐transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls.ConclusionPAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta‐ and/or tau‐dependent models with prominent neuroinflammation.     

Involvement of cytokines in normal CNS development and neurological diseases: Recent progress and perspectives

Cytokines have been recognized to play an important role both in normal development of the brain, when they act as neurotrophic factors, as well as following injury. While both the cytokines and their receptors are synthesized and expressed in the brain normally (albeit at low levels), it has become clear that elevated levels are associated with many neurological disorders. In this review, we have chosen to present the data for only a few of the cytokines, including interleukin-1β, interleukin-3, interleukin-6, interferon-γ, transforming growth factor-β, and tumor necrosis factor-α. Data are presented that suggest roles they may play in human disorders, including stroke, multiple sclerosis, Alzheimer's disease, and several psychiatric disorders. The results in human disease are compared with results obtained in a variety of transgenic animal models. The mouse models have very different disorders depending on whether a cytokine is overexpressed either peripherally or in either astrocytes or neurons. The potential significance of this to the understanding of human disease is discussed. J. Neurosci. Res. 52:7–16, 1998. Published 1998 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

The problem of genotype and sex differences in life expectancy in transgenic AD mice

The lifespan of mice shows genotype, sex and laboratory effects, but little is known about genotype or sex differences in life expectancy of mouse models of Alzheimer's disease (AD). This paper examines the lifespan of males and females of different mouse models of AD and their wildtype strains. Genotype and sex dependent differences in longevity have important implications for designing experiments with Alzheimer's mouse models, comparing genotype and sex differences in aging mouse models, designing drug treatment regimes and the translation of mouse data to human clinical studies. We conclude that the concept of aging and age-related disorders in mice must be reconsidered based on genotype and sex differences in mouse life expectancy data. Use of concepts such as relative age, prospective lifespan and proportion of lifespan remaining should be included in studies of age-related changes in mouse brains and behavior. Finally, measures such as the Frailty Index, which is independent of chronological age might be used to determine a common scale of aging for all mouse strains.     

Locomotor behavior of dopamine D1 receptor transgenic/D2 receptor deficient hybrid mice

Mice that incorporate the dopamine D1 receptor transgene controlled by the D1 receptor promoter exhibit a marked increase of D1 binding in several extra-striatal brain regions and show a paradoxical hypokinetic response to D1 agonist [Exp. Neurol. 157 (1999) 169]. The agonist-induced locomotor behavior of D1 receptor transgenic mice is similar to baseline locomotor activity manifested by D2 receptor deficient mice [J. Neurosci. 18 (1998) 3470]. The similarity between these two behavioral phenotypes raised the possibility that stimulation of the over-expressed D1 receptors in the transgenic mice could cause a suppression of D2 receptor responses that manifest in hypokinesia. Alternatively, the similar phenotypes could result from altered D1/D2 receptor balance in both animal models. Two different approaches were undertaken to test these alternative hypotheses. (1) The effects of pharmacological blockade of D2 receptors on D1 agonist-stimulated hypokinesia of the D1 over-expressing animals were investigated. (2) The behavioral phenotype of hybrid D1 receptor over-expressing/D2 receptor deficient mice generated by crossbreeding the D2 knockout mice and the D1 transgenic animals was studied. The results of these studies suggested that the hypomotor response of the D1 transgenic mice was not a result of an interaction of the over-expressed D1 receptors with the native D2 receptors and that over-expressed D1 receptors likely mediate hypokinesia in the D1 transgenic animals. Considering the significance of the D1 dopamine receptor as a therapeutic target for Parkinson's disease, this D1 receptor over-expressing model provides an important experimental system to probe the basis for altered behavioral responses following stimulation of transgenetically up-regulated receptors.     

Verbal aggression in Alzheimer's disease. Clinical, functional and neuropsychological correlates

OBJECTIVES: To determine the clinical, functional and neuropsychological correlates of verbal aggression in Alzheimer's disease in a group of consecutive first attendees to a memory clinic. METHODS: 150 people were evaluated and diagnosed as suffering with probable Alzheimer's disease. These people were tested using the Behave-AD for the presence of verbal aggression, delusions, depression and agitation. They were also assessed with cognitive, functional and neuropsychological scales. RESULTS: Twenty-eight per cent of this group of Alzheimer patients had exhibited some verbal aggression in the preceding month. Male gender (p = 0.022), the presence of paranoid and delusional ideation (p = 0.003) and agitation (p = 0.042) were significantly associated with verbal aggression in a stepwise backward logistic regression analysis. CONCLUSION: The presence of verbal aggression should prompt the clinician to search for delusional ideation, which may respond to pharmacotherapy.     

Reduction of hippocampal N‐acetyl aspartate level in aged APPSwe/PS1dE9 transgenic mice is associated with degeneration of CA3 pyramidal neurons

Age‐related metabolic changes in the hippocampus of APP_Swe/PS1_dE9 mice were measured with long echo‐time in vivo ¹H‐magnetic resonance spectroscopy (¹H‐MRS). Thioflavine S staining and Nissl staining were used to characterize deposition of Aβ aggregates and neuronal degeneration in the transgenic animals, respectively. The results showed that the APP_Swe/PS1_dE9 mice had significantly decreased hippocampal N‐acetyl aspartate (NAA)/total creatine (tCr) level at 16 months of age, which was associated with degeneration of and intracellular deposition of thioflavine S‐positive materials in hippocampal CA3 pyramidal neurons. The results of this study provide direct evidence showing association among Aβ pathology (intracellular deposition of thioflavine S‐positive materials), neuronal degeneration, and metabolic changes observable with in vivo ¹H‐MRS in the hippocampus of APP_Swe/PS1_dE9 mice. © 2010 Wiley‐Liss, Inc.     

Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function

The apolipoprotein E (apoE) epsilon 4 allele (apoE4) is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A role for apoE in regeneration of synaptic circuitry after neural injury has been shown in several in vitro studies in which apoE3 supports neuronal sprouting better than apoE4. We evaluated sprouting in an in vitro mouse organotypic hippocampal slice culture system derived from transgenic mice expressing apoE3 or apoE4, in which apoE-dependent granule cell mossy fiber sprouting in the presence of apoE4 is only 51% of the level of apoE3. Sprouting supported by apoE4 had a dose response opposite that by supported by apoE3: although increasing E3 expression increased sprouting, increasing E4 expression decreased sprouting, suggesting that the defect in E4 in supporting neuronal sprouting is a gain-of-negative activity. These results may have important pharmacogenomic implications for AD therapies that modulate apoE expression levels.