Targeting redox-altered plasticity to reactivate synaptic function: A novel therapeutic strategy for cognitive disorder

Redox-altered plasticity refers to redox-dependent reversible changes in synaptic plasticity

Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice

ProBiotic-4 is a probiotic preparation composed of , , , and . This study aims to investigate the effects of ProBiotic-4 on the microbiota-gut-brain axis and cognitive deficits, and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8 (SAMP8) mice. ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks. We observed that ProBiotic-4 significantly improved the memory deficits, cerebral neuronal and synaptic injuries, glial activation, and microbiota composition in the feces and brains of aged SAMP8 mice. ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood-brain barrier, decreased interleukin-6 and tumor necrosis factor- at both mRNA and protein levels, reduced plasma and cerebral lipopolysaccharide (LPS) concentration, toll-like receptor 4 (TLR4) expression, and nuclear factor-B (NF-B) nuclear translocation in the brain. In addition, not only did ProBiotic-4 significantly decreased the levels of -H2AX, 8-hydroxydesoxyguanosine, and retinoic-acid-inducible gene-I (RIG-I), it also abrogated RIG-I multimerization in the brain. These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota-gut-brain axis and cognitive function in aging, and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-B signaling pathway and inflammatory responses.

Epidemiology of Age-Associated Memory Impairment

It has been widely known that the elderly suffer very mild cognitive impairment including memory function that cannot satisfy the criteria of dementia. Koivisti and Hannien et al reported that the prevalences of age-associated memory impairment and age-associated cognitive decline were 38.6% and 26.6%, respectively. The prevalence rate of male was more than that of female and the prevalence rate was increased in younger elderly. The risk factors of age-related cognitive decline were age and myocardiac infarction whereas education and smoking decreased the risk of age-related cognitive decline. The small portion of age-associated memory impairment progressed toward dementia but the most of them were nonprogressive. The probability of progression toward dementia could be predicted by detailed neurocognitive function test. The further epidemiologic studies will reveal the nature of age-associated memory impairment.

Neurobiology of Age-Associated Memory Impairment

The diagnostic concept of age-associated memory impairment (AAMI) suggests that clinically recognized memory dysfunction could be a feature of normal aging. Although the memory impairment associated with aging is well recognized, underlying neurobiological mechanisms of cognitive decline remain unclear. There are a number of age-related structural and physiological changes in the brain that could have implications for cognitive decline in the elderly. The impact of these age-related changes in the brain on cognition has been studied using postmortem neurochemical, neuropathological findings or neuroimaging techniques. The available evidence from studies in aged and demented humans suggested that cognitive deficits related to aging might involve concomitant alterations of various neurochemical systems in several brain regions such as the striatum, the hippocampus or the cortex. It also seems that these alterations occur in a complex way which affects dopaminergic, glutamaterigc and serotonergic neurotnasmission in addition to the loss of cholinergic neurons in the basal forebrain, However, data collected to explain the mechanism of AAMI are still limited, the definite interpretation of these findings must await futher studies.

Conceptual and Clinical Overview on Age-Associated Memory Impairment

It is sufficient to justify distinguishing age-appropriate and age-inappropriate forms of age-related memory decline. The former, of which AAMI is an example, represents a normal age-related phenomenon, whereas the latter, the true descendent of benign senescent forgetfulness, is by definition abnormal and possibly, pathological. Whether age-inappropriate forgetfulness is progressive, whether it can be distinguished from other concepts of mild cognitive decline by virtue of being specific to memory, and whether it is qualitatively different from normal memory or merely worse is not yet certain. The prevalence of age-inappropriate forgetfulness is undetermined, but it is certainly less common than AAMI. The construct of AAMI was introduced by an NIMH work group. It was the group's declared intention to facilitate communication and stimulate research into late-life memory loss, particularly its treatment. Completely satisfactory diagnostic criteria do not yet exist for AAMI. Improved criteria would take an individual's overall level of intellectual functioning or educational background into account when setting the standard against which to rate memory, distinguish age-appropriate from age-inappropriate decline. AAMI differs from BSF in several points. First, the AAMI criteria define impairment with respect to healthy young adult levels, not to those of the older individual's age peers as was implied in the description of BSF. Second, the term AAMI is non-specific with regard to etiology and does not necessarily imply that the disorder is non-progressive. Thus, patients whose memory impairment is subsequently shown to be the earliest stage of a dementing illness are not necessarily excluded from the category of AAMI, and it is sensible to ask how often AAMI is, in fact, a dementia prodrome.

Effectiveness of Huperzine A,Nimodipine and the combinative utilization to age associated memory impairment and influence of those to levels of plasma total antioxidant capacity and calcium of platelet / 临床神经病学杂志

Objective To study the effectiveness of Huperzine A,Nimodipine and the combinative utilization to age associated memory impairment(AAMI) and the influence of those to the plasma total antioxidant capacity(TAC) and calcium of platelet.Methods 140 patients with AAMI were randomly divided into 4 groups(35 cases in each group).Huperzine group administrated with Huperzine A 100 ?g thrice a day;Nimodipine group administrated with Nimodipine 30 mg thrice a day;combined group administrated with Huperzine A 100 ?g twice a day and Nimodipine 30 mg thrice a day;control group administrated with Vitamin B6 10 mg thrice a day.All the cases were treated for 6 weeks.Before and after treatment,the memory function were tested by WMS.The levels of plasma TAC and calcium of platelet were also measured at the same time.Results After treatment,the scores of WMS,the levels of plasma TAC and calcium of platelet in Huperzine A group,Nimodipine group and combined group were higher than before treatment and those in control group(all P