Administration of Aggregated Beta-Amyloid Peptide (25–35) Induces Changes in Long-Term Potentiation in the Hippocampus in Vivo

Intracerebroventricular administration of aggregated -amyloid protein fragment (25–35) (7.5 nmol/ventricle) was followed one month later by significant changes in the dynamics of long-term potentiation in the hippocampus in vivo, expressed as powerful and stable increases in the amplitude of evoked potentials. This phenomenon may be associated with oxidative stress in the hippocampus, which has previously been demonstrated in this model, and, thus, with disturbances in ion homeostasis.     

Changes in Cell Proliferation in the Subventricular Zone of the Brain in Adult Rats Given β-Amyloid Peptide (25–35)

The effects of intracerebroventricular administration of fragment (25–35) of β-amyloid peptide [Aβ(25–35)] on cell proliferation in the subventricular zone of the dentate gyrus of the hippocampus in adult rats were analyzed. Animals received doses of 15 nmol of pre-aggregated Aβ(25–35) or the Aβ(35–25) control peptide, or solvent (sterile water) into the lateral ventricles. On post-injection days 1–5, rats received intraperitoneal injections of the thymidine analog 5-bromo-2’-deoxyuridine (BrdU). BrdU incorporated into DNA was detected immunohistochemically on frontal brain sections six and 12 days after peptide administration. At six days, the numbers of BrdU-containing cells in the subventricular zone showed no differences between the study groups. At 12 days, the total number of BrdU-positive cells decreased significantly in all study groups. At the same time, the number of labeled cells in rats given Aβ(25–35) was significantly greater in this brain zone than in animals given water or the control peptide. Thus, Aβ(25–35) significantly increased cell proliferation in the subventricular zone after intracerebroventricular administration.     

Donepezil Eliminates Suppressive Effects of β-Amyloid Peptide (1-42) on Long-Term Potentiation in the Hippocampus

β-Amyloid peptide 1-42 in a concentration of 200 nM impairs induction of long-term posttetanic potentiation of population spike in CA1 pyramidal neurons in rat hippocampal slices. Application of donepezil, a drug used for the treatment of Alzheimer disease, in a concentration of 1 μM eliminates the suppressive effect of β-amyloid peptide 1-42 on long-term posttenanic potentiation in the hippocampus.     

Central Administration of Amyloid β-Peptide (25–35) and Individual Features of Cognitive Behavior in Rats

The individual characteristics of cognitive behavior induced by intracerebroventricular administration of aggregated amyloid β-peptide (25–35) (Aβ_25–35) were studied. A new approach to evaluating individual features of the actions of Aβ_25–35 was used. Navigational training was performed in a single brief session using random target positions, and training sessions were repeated a few days later. These experiments produced the first indication that cognitive behavior was undamaged in 50% of the rats at the early stage of Aβ_25–35 exposure. The activities of the antioxidant enzymes superoxide dismutase and catalase in the cortex and hippocampus were significantly decreased in animals with and without cognitive impairments. We suggest that phenotypic characteristics may underlie the individual features of the animals’ responses to Aβ. At the early stage, aggregated Aβ may induce a compensatory reaction which prevents impairment of cognitive processes.     

Effects of β-amyloid (25–35) on learning in the common snail

The effects of neurotoxic β-amyloid fragment (25–35) on the formation of behavioral sensitization and a conditioned defensive reflex to food were studied. Administration of β-amyloid (25–35) to common snails before the start of training led to a significant reduction in sensitization of the defensive reaction, weakening of the formation of the conditioned defensive reflex to food, and impairment of memory. These impairments to behavioral plasticity may be mediated by changes in synaptic plasticity previously observed in the presence of β-amyloid. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 57, No. 2, pp. 229–236, March–April, 2007.     

β-Amyloid 25–35 Suppresses the Secretory Activity of the Dopaminergic System in the Rat Brain

Neuroscience and Behavioral Physiology - Dysfunction of the dopaminergic system of the brain may underlie a number of the clinical manifestations of Alzheimer’s disease. Published data...     

Studies of the effects of fragment (25–35) of beta-amyloid peptide on the behavior of rats in a radial maze

Decreases in cognitive functions, particularly long-term (episodic) and working memory, are among the earliest prognostic signs of Alzheimers disease. The toxicity of -amyloid peptide is regarded as a major cause of neurodegeneration and cognitive impairment in this disease. The present report describes studies of the effects of intracerebroventricular administration of -amyloid peptide (25–35) (A(25–35)) on the reproduction of a previously assimilated habit consisting of finding food in an eight-arm radial maze in rats. A (25–35) was given bilaterally at doses of 15 and 30 nmol/animal seven days after preliminary training. Testing was performed 60 days after peptide administration. The results showed that A(25–35) impaired working memory in rats without having any significant effect on the retention of responses. We were unable to demonstrate any relationship between memory impairment and the dose of peptide given. These data provide evidence of the ability of A(25–35) to produce greater degradation of working memory function than long-term memory function.Translated from Zhurnal Vysshei Nervnoi Deyatelnosti, Vol. 54, No. 3, pp. 382–389, May–June, 2004.     

Effects of Hericium erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice

The mushroom Hericium erinaceus has been used as a food and herbal medicine since ancient times in East Asia. It has been reported that H. erinaceus promotes nerve growth factor secretion in vitro and in vivo. Nerve growth factor is involved in maintaining and organizing cholinergic neurons in the central nervous system. These findings suggest that H. erinaceus may be appropriate for the prevention or treatment of dementia. In the present study, we examined the effects of H. erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice. Mice were administered 10 μg of amyloid β(25-35) peptide intracerebroventricularly on days 7 and 14, and fed a diet containing H. erinaceus over a 23-d experimental period. Memory and learning function was examined using behavioral pharmacological methods including the Y-maze test and the novel-object recognition test. The results revealed that H. erinaceus prevented impairments of spatial short-term and visual recognition memory induced by amyloid β(25-35) peptide. This finding indicates that H. erinaceus may be useful in the prevention of cognitive dysfunction.     

Compensatory Changes in Mauthner Neurons in Goldfish Induced by Sensory Stimulation and Application of β-Amyloid

Neuroscience and Behavioral Physiology - Objectives. To study the structure and formation of Mauthner neuron dendrites in goldfish exposed to neurotoxic β-amyloid fragment 25–35 and...     

Delayed–Execute Prospective Memory Performance: The Effects of Age and Working Memory

This study follows the novel delayed-execute prospective memory paradigm, which involves briefly delaying the execution of an intended action, a task that has been shown to produce substantial age effects. During the ongoing task, sentences were presented, and participants had to answer reading-comprehension questions and general knowledge questions. In the prospective memory task, the participant was to press a key after the presentation of a specific cue in the sentences—but not before a subsequent phase of the ongoing task was reached. In contrast to previous studies using older participants taken from very broadly defined age ranges, this study examines development of delayed-execute prospective memory more precisely by examining a total of 4 age groups: a younger age group (age range = 22–31; n = 27), a young-old age group (age range = 60–69; n = 34), a middle-old age group (age range = 70–79; n = 31), and an old-old age group (age range = 80–91; n = 35). This study investigates the dependence of (age-related) delayed-execute prospective memory performance on working memory capacity by disrupting the phonological loop during the delay period as well as its dependence on neuropsychological processes such as inhibitory control and processing speed. The results show that (a) delayed-execute prospective memory particularly declines within the group of older participants, (b) delayed-execute prospective memory is diminished when working memory load is high during the delay period, and (c) age-related performance in delayed-execute prospective memory may be mediated by inhibitory control. The findings are discussed in the context of the frontal lobe hypothesis of cognitive aging.     

Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of β-Amyloid in TH1 and TH17 Versions of Experimental Autoimmune Encephalomyelitis

β-Amyloid 42 (Aβ42) and β-amyloid 40 (Aβ40), major components of senile plaque deposits in Alzheimer's disease, are considered neurotoxic and proinflammatory. In multiple sclerosis, Aβ42 is up-regulated in brain lesions and damaged axons. We found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. Aβ42 and Aβ40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive T helper 1 (T(H)1) or T(H)17 cells. High-dimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo Aβ42 and Aβ40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major proinflammatory cytokines and chemokines were reduced in the blood after Aβ peptide treatment. Protection conferred by Aβ treatment did not require its delivery to the brain: Adoptive transfer with lymphocytes from donors treated with Aβ42 attenuated EAE in wild-type recipient mice, and Aβ deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with Aβ treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of Aβ, there is exacerbated clinical EAE disease progression. Because Aβ42 and Aβ40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.     

Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease

Many individuals with Parkinson''s disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer''s disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.     

Changes in β-Endorphin Level in the Cingulate Cortex in Rats after Peripheral Loperamide and Methylnaloxone Administration at Rest and during Emotional Stress

β-Endorphin content in the extracellular space of rat cingulate cortex was measured using intravital microdialysis followed by ELISA. Intragastric administration of μ-opioid ligands loperamide and methylnaloxone not crossing the blood-brain barrier produced different effects on β-endorphin level: loperamide reduced and methylnaloxone signifi cantly increased the release of β-endorphin into the extracellular space of rat cingulate cortex. Emotional stress caused by immobilization resulted in slight increase in β-endorphin level in the cingulate cortex. Peripheral administration of loperamide (but not methylnaloxone) signifi cantly increased the release of the neuropeptide during stress. These fi ndings support our hypothesis of reciprocal interaction between the central and peripheral compartments of the endogenous opioid system and provide explanations for the anti-stress effects of loperamide.     

Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer's Disease Pathology

Aggregation of β-amyloid (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer's disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF Aβ in the brain of the APPswe/PS1δE9 mouse model of AD before Aβ plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid Aβ in young adult humans with presenilin mutations was also markedly attenuated after Aβ plaque formation. Virtual elimination of Aβ deposits in the mouse brain by active immunization with Aβ(42) normalized the sleep-wake cycle and the diurnal fluctuation of ISF Aβ. These data suggest that Aβ aggregation disrupts the sleep-wake cycle and diurnal fluctuation of Aβ. Sleep-wake behavior and diurnal fluctuation of Aβ in the central nervous system may be functional and biochemical indicators, respectively, of Aβ-associated pathology.     

Autoantibodies to β-Amyloid and Neurotransmitters in Patients with Alzheimer's Disease and Senile Dementia of the Alzheimer Type

The content of autoantibodies to -amyloid protein A_1-42, its neurotoxic fragment A_25-35, and neurotransmitters were studied in the blood of patients with presenile Alzheimer's disease and senile dementia of the Alzheimer type. Significant differences in the relative content of autoantibodies to A_1-42 and autoantibodies to biogenic amines were demonstrated. These results can be used for the development of a biochemical method for differential diagnosis of Alzheimer dementias.