Effects of medicinal plants on Alzheimer＇s disease and memory deficits

Alzheimer's disease is an age-related neurodegenerative disorder characterized by memory deficits. Various studies have been carried out to find therapeutic approaches for Alzheimer's disease. However, the proper treatment option is still not available. There is no cure for Alzheimer's disease, but symptomatic treatment may improve the memory and other dementia related problems. Traditional medicine is practiced worldwide as memory enhancer since ancient times. Natural therapy including herbs and medicinal plants has been used in the treatment of memory deficits such as dementia, amnesia, as well as Alzheimer's disease since a long time. Medicinal plants have been used in different systems of medicine, particularly Unani system of medicines and exhibited their powerful roles in the management and cure of memory disorders. Most of herbs and plants have been chemically evaluated and their efficacy has also been proven in clinical trials. However, the underlying mechanisms of actions are still on the way. In this paper, we have reviewed the role of different medicinal plants that play an important role in the treatment of Alzheimer's disease and memory deficits using conventional herbal therapy.

Effects of triptolide on hippocampal microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer＇s disease

The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques,which in turn induce neuroinflammation in the brain.Triptolide,a natural extract from the vine-like herb Tripterygium wilfordii Hook F,has potent anti-inflammatory and immunosuppressive efficacy.Therefore,we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease.We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice(aged 4–4.5 months) for 45 days.Unbiased stereology analysis found that triptolide dose-dependently reduced the total number of microglial cells,and transformed microglial cells into the resting state.Further,triptolide(5 μg/kg/d) also reduced the total number of hippocampal astrocytes.Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS1 double transgenic mice with Alzheimer's disease.

Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer＇s disease

Alzheimer's disease(AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.

Neurofibrillary tangles in Alzheimer＇s disease： elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics

As a key contributor to memory storage,the synapse is one of the earliest affected neuronal components in Alzheimer′s disease(AD).Under physiological conditions,the synaptic connections between neurons undergo activity-dependent functional and morphological re-organisation.This dynamic,‘plastic’neural ability critically depends on the structural integrity of the synapse.Thus,proteins that are implicated in preserving the organisation and dynamics of synaptic connections。

Heterocyclic compounds as key structures for the interaction with old and new targets in Alzheimer＇s disease therapy

Nowadays, Alzheimer's disease(AD) is widely recognized as a real social problem. In fact, only five drugs are FDA approved for the therapy of this widespread neurodegenerative disease, but with low results so far. Three of them(rivastigmine, donepezil and galantamine) are acetylcholinesterase inhibitors, memantine is a N-methyl-D-aspartate receptor antagonist, whereas the fifth formulation is a combination of donepezil with memantine. The prevention and treatment of AD is the new challenge for pharmaceutical industry, as well as for public institutions, physicians, patients, and their families. The discovery of a new and safe way to cure this neurodegenerative disease is urgent and should not be delayed further. Because of the multiple origin of this pathology, a multi-target strategy is currently strongly pursued by researchers. In this review, we have discussed new structures designed to better the activity on the classical AD targets. We have also examined old and new potential drugs that could prove useful future for the therapy of the pathology by acting on innovative, not usual, and not yet fully explored targets like peroxisome proliferator-activated receptor(PPARs).

Distinguishing normal brain aging from the development of Alzheimer＇s disease：inflammation,insulin signaling and cognition

As populations age, prevalence of Alzheimer's disease(AD) is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.

Compound of icariin,astragalus,and puerarin mitigates iron overload in the cerebral cortex of Alzheimer＇s disease mice

Increasing evidence indicates that disruption of normal iron homeostasis may contribute to pathological development of Alzheimer's disease.Icariin,astragalus,and puerarin have been shown to suppress iron overload in the cerebral cortex and improve spatial learning and memory disorders in Alzheimer's disease mice,although the underlying mechanism remains unclear.In the present study,APPswe/PS1ΔE9 transgenic mice were administered icariin,astragalus,and puerarin(120,80,and 80 mg/kg,respectively,once a day,for 3 months).Iron levels were detected by flame atomic absorption spectroscopy.Interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were measured in the cerebral cortex by enzyme linked immunosorbent assay.Glutathione peroxidase and superoxide dismutase activity and malondialdehyde content were determined by colorimetry.Our results demonstrate that after treatment,iron levels and malondialdehyde content are decreased,while glutathione peroxidase and superoxide dismutase activities are increased.Further,interleukin-1β,interleukin-6,and tumor necrosis factor-α levels were reduced.These results confirm that compounds of icariin,astragalus,and puerarin may alleviate iron overload by reducing oxidative stress and the inflammatory response.

High-frequency electroacupuncture evidently reinforces hippocampal synaptic transmission in Alzheimer＇s disease rats

The frequency range of electroacupuncture in treatment of Alzheimer's disease in rats is commonly 2–5 Hz(low frequency) and 50–100 Hz(high frequency). We established a rat model of Alzheimer's disease by injecting β-amyloid 1–42(Aβ_(1–42)) into the bilateral hippocampal dentate gyrus to verify which frequency may be better suited in treatment. Electroacupuncture at 2 Hz or 50 Hz was used to stimulate Baihui(DU20) and Shenshu(BL23) acupoints. The water maze test and electrophysiological studies demonstrated that spatial memory ability was apparently improved, and the ranges of long-term potentiation and long-term depression were increased in Alzheimer's disease rats after electroacupuncture treatment. Moreover, the effects of electroacupuncture at 50 Hz were better than that at 2 Hz. These findings suggest that high-frequency electroacupuncture may enhance hippocampal synaptic transmission and potentially improve memory disorders in Alzheimer's disease rats.

Use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease

This review summarizes and describes the use of curcumin in diagnosis,prevention,and treatment of Alzheimer's disease.For diagnosis of Alzheimer's disease,amyloid-β and highly phosphorylated tau protein are the major biomarkers.Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β.Because of its multi-target effects,curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease,hypertension,and hyperlipidemia.For prevention and treatment of Alzheimer's disease,curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels,mitochondria,and synapses,reduce risk factors for a variety of chronic diseases,and decrease the risk of Alzheimer's disease.The effect of curcumin on Alzheimer's disease involves multiple signaling pathways:anti-amyloid and metal iron chelating properties,antioxidation and anti-inflammatory activities.Indeed,there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer's disease.

High-frequency (50 Hz) electroacupuncture ameliorates cognitive impairment in rats with amyloid beta 1–42-induced Alzheimer＇s disease

Acupuncture has been shown to ameliorate cognitive impairment of Alzheimer’s disease.Acupoints and stimulation frequency influence the therapeutic effect of electroacupuncture.Rat models of Alzheimer’s disease were established by injecting amyloid beta 1–42(Aβ_(1–42))into the bilateral lateral ventricles.Electroacupuncture at 2,30,and 50 Hz was carried out at Baihui(GV20;15°obliquely to a depth of 2mm)and Shenshu(BL23;perpendicularly to 4–6 mm depth),once a day for 20 minutes(each),for 15 days,taking a break every 7 days.The Morris water maze test was conducted to assess the learning and memory.The expression levels of glycogen synthase kinase-3β(GSK-3β),p Ser9-GSK-3β,p Tyr216-GSK-3β,amyloid precursor protein and Aβ_(1–40) in the hippocampus were determined by western blot assay.Results demonstrated that electroacupuncture treatment at different frequencies markedly improved learning and memory ability,increased synaptic curvatures,decreased the width of synaptic clefts,thickened postsynaptic densities,and downregulated the expression of GSK-3β,amyloid precursor protein,and Aβ_(1–40).pSer9-GSK-3βexpression markedly decreased,while p Tyr216-GSK-3βexpression increased.High-frequency(50 Hz)electroacupuncture was more effective than low(2 Hz)or medium-frequency(30 Hz)electroacupuncture.In conclusion,electroacupuncture treatment exerts a protective effect against Aβ_(1–42)-induced learning and memory deficits and synapse-ultrastructure impairment via inhibition of GSK-3βactivity.Moreover,high-frequency electroacupuncture was the most effective therapy.

Amyloid β and free heme：bloody new insights into the pathogenesis of Alzheimer＇s disease

The cerebral formation of Amyloid β(Aβ) is a critical pathological feature of Alzheimer's disease(AD).An accumulation of this peptide as senile plaques(SP) was already reported by Alois Alzheimer,the discoverer of the disease.Yet the exact contribution of Aβ to AD development remains elusive.Moreover,while extensive cerebral Aβ formation leads to fibril formation in many species,AD-like symptoms apparently depend on the highly conserved N-terminal residues R5,Y10 and H13.The amino acids were also shown to lead to the formation of Aβ-heme complexes,which exhibit peroxidase activity in the presence of H_2O_2.Taking together these observations we propose that the formation and enzymatic activity of the named complexes may represent an essential aspect of AD pathology.Furthermore,Aβ is also known to lead to cerebral micro-vessel destruction(CAA) as well as to hemolytic events.Thus we suggest that the Aβ-derived cerebral accumulation of blood-derived free heme represents a likely precondition for the subsequent formation of Aβ-heme complexes.

Long-term acupuncture treatment has a multitargeting regulation on multiple brain regions in rats with Alzheimer＇s disease：a positron emission tomography study

The acute effect of acupuncture on Alzheimer’s disease,i.e.,on brain activation during treatment,has been reported.However,the effect of long-term acupuncture on brain activation in Alzheimer’s disease is unclear.Therefore,in this study,we performed long-term needling at Zusanli(ST36)or a sham point(1.5 mm lateral to ST36)in a rat Alzheimer’s disease model,for 30 minutes,once per day,for 30 days.The rats underwent 18F-fluorodeoxyglucose positron emission tomography scanning.Positron emission tomography images were processed with SPM2.The brain areas activated after needling at ST36 included the left hippocampus,the left orbital cortex,the left infralimbic cortex,the left olfactory cortex,the left cerebellum and the left pons.In the sham-point group,the activated regions were similar to those in the ST36 group.However,the ST36 group showed greater activation in the cerebellum and pons than the sham-point group.These findings suggest that long-term acupuncture treatment has targeted regulatory effects on multiple brain regions in rats with Alzheimer’s disease.