Induced Th2 dominant immune response in APPswe, PSEN1dE9 transgenic mice after nasal immunization with an adenoviral vector encoding 10 tandem repeats of beta-amyloid 3-10

Immunotherapy for Alzheimer＇s disease （AD） is effective in improving cognitive function in transgenic mouse models of AD. Because the AN1792 [beta-amyloid （Aβ） 1-42] vaccine was halted because of T cell mediated meningoencephalitis, many scientists are searching for a nove） vaccine to avoid the T cell mediated immune response caused by the Aβ1-42. Importantly, the time when the immunization is begun can influence the immune effect. In this study, an adenovirus vaccine was constructed containing 10 x Aβ3-10 repeats and gene adjuvant CpG DNA. Transgenic AD mice were immunized intranasally for 3 months. After 10 × Aβ3-10 vaccine immunization, high titers of anti-Aβ42 IgG1 predominant antibodies were induced. In spatial learning ability and probe tests, the 10 × Aβ3-10 immunized mice showed significantly improved memories compared to control mice. The 10 × Aβ3-10 vaccine resulted in a robust Th2 dominant humoral immune response and reduced learning deficits in AD mice. In addition, the 10 × Aβ3-10 vaccine might be more efficient if administered before Aβ aggregation at an early stage in the AD mouse brain. Thus, the adenovirus vector encoding 10 × Aβ-10 is a promising vaccine for AD.

Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer's disease

Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.

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-dependent- ly 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/PS 1 double transgenic mice with Alzheimer＇s disease.

Alzheimer's disease: the silver tsunami of the 21^(st) century

Alzheimer＇s disease（AD）, a fatal progressive neurodegenerative disorder, has no cure to date. One of the causes of AD is the accumulation of amyloid-beta 42（Aβ42） plaques, which result in the onset of neurodegeneration. It is not known how these plaques trigger the onset of neurodegeneration. There are several animal models developed to（i） study etiology of disease,（ii） look for genetic modifiers, and（iii） identify chemical inhibitors that can block neurodegeneration and help to find cure for this disease. An insect model of Drosophila melanogaster has also provided new insights into the disease. Here we will discuss the utility of the Drosophila eye model to study Alzheimer＇s disease.

Natural polyphenols effects on protein aggregates in Alzheimer＇s and Parkinson＇s prion-like diseases

Alzheimer＇s and Parkinson＇s diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposits are amyloid peptide and tau for Alzheimer＇s disease, α-synuclein and synphilin-1 for Parkinson＇s disease. Drugs currently proposed to treat these pathologies do not prevent neurodegenerative processes and are mainly symptomatic therapies. Molecules inducing inhibition of aggregation or disaggregation of these proteins could have beneficial effects, especially if they have other beneficial effects for these diseases. Thus, several natural polyphenols, which have antioxidative, anti-inflammatory and neuroprotective properties, have been largely studied, for their effects on protein aggregates found in these diseases, notably in vitro. In this article, we propose to review the significant papers concerning the role of polyphenols on aggregation and disaggregation of amyloid peptide, tau, α-synuclein, synphilin-1, suggesting that these compounds could be useful in the treatments in Alzheimer＇s and Parkinson＇s diseases.

From cradle to grave: neurogenesis, neuroregeneration and neurodegeneration in Alzheimer’s and Parkinson’s diseases

Two of the most common neurodegenerative disorders-Alzheimer’s and Parkinson’s diseases-are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein accumulation.The intracellular aggregation of hyper-phosphorylated tau and the extracellular aggregation of amyloid beta plaques form the basis of Alzheimer’s disease pathology.The major hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta,following the formation of Lewy bodies,which consists primarily of alpha-synuclein aggregates.However,the discrete mechanisms that contribute to neurodegeneration in these disorders are still poorly understood.Both neuronal loss and impaired adult neurogenesis have been reported in animal models of these disorders.Yet these findings remain subject to frequent debate due to a lack of conclusive evidence in post mortem brain tissue from human patients.While some publications provide significant findings related to axonal regeneration in Alzheimer’s and Parkinson’s diseases,they also highlight the limitations and obstacles to the development of neuroregenerative therapies.In this review,we summarize in vitro and in vivo findings related to neurogenesis,neuroregeneration and neurodegeneration in the context of Alzheimer’s and Parkinson’s diseases.

Potential neuroprotection by Dendrobium nobile Lindl alkaloid in Alzheimer's disease models

At present,treatments for Alzheimer's disease can temporarily relieve symptoms but cannot prevent the decline of cognitive ability and other neurodegenerative changes.Dendrobium nobile Lindl alkaloid is the main active component of Dendrobium nobile Lindl.Dendrobium nobile Lindl alkaloid has been shown to resist aging,prolong life span,and exhibit immunomodulatory effects in animals.This review summarizes the mechanisms behind the neuroprotective effects reported in Alzheimer's disease animal models.The neuroprotective effects of Dendrobium nobile Lindl alkaloid have not been studied in patients.The mechanisms by which Dendrobium nobile Lindl alkaloid has been reported to improve cognitive dysfunction in Alzheimer's disease animal models may be associated with extracellular amyloid plaque production,regulation of tau protein hyperphosphorylation,inhibition of neuroinflammation and neuronal apoptosis,activation of autophagy,and enhanced synaptic connections.

ApoE2 and Alzheimer's disease:time to take a closer look

Alzheimer’s disease（AD）is the most common form of dementia among the elderly.It currently affects approximately 5.1 million Americans,a number predicted to triple by 2050.AD is clinically manifested as progressive loss of memory and cognitive function,and is characterized pathologically by the formation of amyloid-beta（Aβ）plaques and neurofibrillary tangles（NFT）.Since its discovery in 1906,

The use of localized proteomics to identify the drivers of Alzheimer's disease pathogenesis

Alzheimer’s disease（AD）is broadly defined by dementia and the presence of specific neuropathological features in the brain（amyloid plaques,neurofibrillary tangles（NFTs）and congophilic amyloid angiopathy）.However,the rate of disease progression,type of cognitive impairment,and extent of neuropathology vary widely in patients with AD（Murray et al.,2011）.

Early Activation of Astrocytes does not Affect Amyloid Plaque Load in an Animal Model of Alzheimer's Disease

Astrocytes are closely associated with Alzheimer’s disease(AD). However, their precise roles in AD pathogenesis remain controversial. One of the reasons behind the different results reported by different groups might be that astrocytes were targeted at different stages of disease progression. In this study, by crossing h APP(human amyloid precursor protein)-J20 mice with a line of GFAP-TK mice, we found that astrocytes were activated specifically at an early stage of AD before the occurrence of amyloid plaques, while microglia were not affected by this crossing. Activation of astrocytes at the age of 3–5 months did not affect the proteolytic processing of hAPP and amyloid plaque loads in the brains of hAPP-J20 mice. Our data suggest that early activation of astrocytes does not affect the deposition of amyloid b in an animal model of AD.

Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs

Alzheimer’s disease(AD)is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily lives.While the etiology of AD remains an enigma,excessive accumulation ofβ-amyloid peptide(Aβ)is widely believed to induce pathological changes and cause dementia in brains of AD patients.BACE1 was discovered to initiate the cleavage of amyloid precursor protein(APP)at theβ-secretase site.Only after this cleavage doesγ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ.Hence,blocking BACE1 proteolytic activity will suppress Aβgeneration.Due to the linkage of Aβto the potential cause of AD,extensive discovery and development efforts have been directed towards potent BACE1 inhibitors for AD therapy.With the recent breakthrough in developing brain-penetrable BACE1 inhibitors,targeting amyloid deposition-mediated pathology for AD therapy has now become more practical.This review will summarize various strategies that have successfully led to the discovery of BACE1 drugs,such as MK8931,AZD-3293,JNJ-54861911,E2609 and CNP520.These drugs are currently in clinical trials and their updated states will be discussed.With the promise of reducing Aβgeneration and deposition with no alarming safety concerns,the amyloid cascade hypothesis in AD therapy may finally become validated.

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer's Disease

Alzheimer＇s disease （AD） is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflam- mation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PSI/tau triple-trans- genic AD mice （3xTg-AD mice） and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofib- rillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expres- sion levels of hippocampal protein kinase A-cAMP response element-binding protein （PKA-CREB） and p38- mitogen-activated protein kinases （MAPK） also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB- MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.