Alzheimer's disease (AD) is the most prevalent form of age-related dementia in the world, and its main pathological features consist of amyloid-β (Aβ) plaque deposits and neurofibrillary tangles ...formed by hyperphosphorylated tau protein. So far, only a few AD treatments approved have been applied in the clinic, but the effects of these drugs are limited only for partial symptomatic relief to patients with AD and are unable to alter AD progression. Later, all efforts for AD treatments with targeting the pathogenic factors were unsuccessful over the past decades, which suggested that the pathogenesis of AD is complex. Recently, disease-modifying therapies (DMTs) that can change the underlying pathophysiology of AD, with anti-Aβ monoclonal antibodies (mabs) (e.g., aducanumab, bapineuzumab, gantenerumab, solanezumab, and lecanemab) have been developed successively and conducted in clinical trials based on the theory that a systemic failure of cell-mediated Aβ clearance contributes to AD occurrence and progression. In the review, we summarized recent studies on the therapeutic effects and clinical trial results of these mabs in patients with AD. Specifically, we focused on the discussion of the impact of aducanumab and lecanemab on AD pathology and clinical profiles. The review provides a possible evidence for applying immunotherapy with anti-Aβ mabs in AD and analyzes lessons learned from these clinical trials in order to further study the therapeutic and adverse effects of these anti-Aβ mabs on AD.
A key pathological factor of Alzheimer's disease (AD), the most prevalent form of age-related dementia in the world, is excessive β-amyloid protein (Aβ) in extracellular aggregation in the brain. And ...in the peripheral blood, a large amount of Aβ is derived from platelets. So far, the causality between the levels of peripheral blood Aβ and its aggregation in the brain, particularly the role of the peripheral blood Aβ in the pathology of AD, is still unclear. And the relation between the peripheral blood Aβ and tau tangles of brain, another crucial pathologic factor contributing to the pathogenesis of AD, is also ambiguous. More recently, the anti-Aβ monoclonal antibodies are approved for treatment of AD patients through declining the peripheral blood Aβ mechanism of action to enhance plasma and central nervous system (CNS) Aβ clearance, leading to a decrease Aβ burden in brain and improving cognitive function, which clearly indicates that the levels of the peripheral blood Aβ impacted on the Aβ burden in brain and involved in the pathogenesis of AD. In addition, the role of peripheral innate immune cells in AD remains mostly unknown and the results obtained were controversial. In the present review, we summarize recent studies on the roles of peripheral blood Aβ and the peripheral innate immune cells in the pathogenesis of AD. Finally, based on the published data and our own work, we believe that peripheral blood Aβ plays an important role in the development and progression of AD by impacting on the peripheral innate immune cells.
Abstract Alzheimer´s disease (AD) is common age-associated dementia with neurodegeneration. The pathogenesis of AD is complex and still remains unclear. The inflammation, amyloid β (Aβ) and ...neurofibrillary tangles as well misfolded tau protein in brain may contribute to the occurrence and development of AD. Compared with tau protein, Aβ is less toxic. So far all efforts made in the treatments of AD with targeting these pathogenic factors were unsuccessful over past decades. Recently many studies demonstrated that changes of intestinal environment and gut microbiota via gut-brain axis pathway can cause neurological disorders, such as AD, which may be involved in the pathogenesis of AD. Thus, the remodeling the gut microbiota by various ways to maintain their balance might be a novel therapeutic strategy for AD. In the review, we analyze the characteristics of gut microbiota and its dysbiosis in AD and its animal models, and investigate the possibility of targeting the gut microbiota in treatment of the patients with AD in the future.
Background
There are no effective therapies to prevent the occurrence and progression of vertebrobasilar dolichoectasia (VBD). In this study, we investigated the relationship between serum levels of ...lipoprotein-associated phospholipase A2 (Lp-PLA2) and the occurrence and progression of VBD.
Methods
Sixty (60) cases without VBD and ischemia stroke were considered as Group A, 100 cases with VBD were further divided into Group B (VBD without ischemic stroke,
n
= 54) and Group C (VBD with first ever acute posterior circulation ischemic stroke,
n
= 46). Demographic data (such as gender and age) and past medical history (such as hypertension, diabetes, and smoking history) were collected. The levels of serum low-density lipoprotein cholesterol (LDL-C), hypersensitivity C reactive protein (hs-CRP), glycosylated hemoglobin (HbAlc), homocysteine (HCY), uric acid (UA), fibrinogen (Fib), and Lp-PLA2, etc. were measured. Logistic regression analysis was used to assess the related factors of VBD and ischemic stroke secondary to VBD.
Results
Logistic multivariate regression analysis showed that only age and the level of serum Lp-PLA2 were significantly higher in group B than those in group A (
P
< 0.012,
P
< 0.001, respectively), however, only the level of serum Lp-PLA2 was significantly higher in group C than those in group B (
P
< 0.001).
Conclusions
The serum marker Lp-PLA2 is an independent risk factor for the occurrence of VBD and the progression of VBD to posterior circulation ischemic stroke. Whether intervening on atherosclerosis could prevent the occurrence and development of VBD needs to be further studied.
Research on light modulation has typically examined the wavelength, intensity, and exposure time of light, and measured rhythm, sleep, and cognitive ability to evaluate the regulatory effects of ...light variables on physiological and cognitive functions. Although the frequency of light is one of the main dimensions of light, few studies have attempted to manipulate it to test the effect on brain activation and performance. Recently, 40-Hz light stimulation has been proven to significantly alleviate deficits in gamma oscillation of the hippocampus caused by Alzheimer's disease. Although this oscillation is one of the key functional characteristics of performing memory tasks in healthy people, there is no evidence that 40-Hz blue light exposure can effectively regulate brain activities related to complex cognitive tasks. In the current study, we examined the difference in the effects of 40-Hz light or 0-Hz light exposure on brain activation and functional connectivity during a recognition memory task. Through joint augmentation of visual area activation, 40-Hz light enhanced brain areas mostly in the limbic system that are related to memory, such as the hippocampus and thalamus. Conversely, 0-Hz light enhanced brain areas mostly in the prefrontal cortex. Additionally, functional connection analysis, with the hippocampus as the seed point, showed that 40-Hz light enhanced connection with the superior parietal lobe and reduced the connection with the default network. These results indicate that light at a frequency of 40 Hz can change the activity and functional connection of memory-related core brain areas. They also indicate that in the use of light to regulate cognitive functions, its frequency characteristics merit attention.
Abstract
More and more evidences are proving that microglia play a crucial role in the pathogenesis of Alzheimer’s disease (AD) and the plasma Aβ
1-42
levels significantly increased 15 years before ...the onset of dominantly inherited AD. However, the effects of high plasma levels of Aβ
1-42
on mononuclear macrophage, the peripheral counterparts of microglia, remain unclear. In the present study, we used APP/PS1 transgenic (Tg) mice and a parabiotic model of wild type (Wt) mice and Tg mice (Parabiotic Wt-Tg, Pa (Wt-Tg)) to investigate the effects of high plasma levels of Aβ
1-42
on peripheral mononuclear macrophage. Our results showed that in the early stage of Tg mice (7 months) and Pa (Wt-Tg) mice (4 months), the proportions of pro-inflammatory macrophages in peritoneal cavity, myeloid derived suppressor cells (MDSCs) in spleen, granulocyte-monocyte progenitors (GMPs) in bone marrow, and the plasma levels of interleukin-6 (IL-6) were significantly decreased. While the proportions of pro-inflammatory macrophages, MDSCs, GMPs, and the plasma levels of IL-6 and tumor necrosis factor (TNF)-α, as well as the numbers of bone marrow-derived macrophages (BMDMs) in mice brain were increased in the late stage of Tg mice (11 months) and Pa (Wt-Tg) mice (8 months). In addition, the proportions of monocytes in spleen and the proliferation of bone marrow cells (BMCs) were enhanced consistently, and the phagocytic function of macrophages kept stably after high plasma levels of Aβ
1-42
sustaining stimulation. These results demonstrated that high plasma levels of Aβ
1-42
play a biphasic regulating role at different stages of the disease, namely inhibiting effects on peripheral pro-inflammatory macrophages in the early stage of AD model, while promoting effects in the late stage of AD model. The mechanism behind this may be associated with their effects on MDSCs in spleen and myeloid progenitor cells in bone marrow. Therefore, intervening the effects of plasma Aβ
1-42
on pro-inflammatory macrophages might offer a new therapeutic approach to AD.
As the important factors in cognitive function, dietary habits and metal exposures are interactive with each other. However, fewer studies have investigated the interaction effect of them on ...cognitive dysfunction in older adults.
2,445 registered citizens aged 60–85 years from 51 community health centers in Luohu District, Shenzhen, were recruited in this study based on the Chinese older adult cohort. All subjects underwent physical examination and Mini-cognitive assessment scale. A semi quantitative food frequency questionnaire was used to obtain their food intake frequency, and 21 metal concentrations in their urine were measured.
Elastic-net regression model, a machine learning technique, identified six variables that were significantly associated with cognitive dysfunction in older adults. These variables included education level, gender, urinary concentration of arsenic (As) and cadmium (Cd), and the frequency of monthly intake of egg and bean products. After adjusting for multiple factors, As and Cd concentrations were positively associated with increased risk of mild cognitive impairment (MCI) in the older people, with OR values of 1.19 (95% CI: 1.05–1.42) and 1.32 (95% CI: 1.01–1.74), respectively. In addition, older adults with high frequency of egg intake (≥30 times/month) and bean products intake (≥8 times/month) had a reduced risk of MCI than those with low protein egg intake (<30 times/month) and low bean products intake (<8 times/month), respectively. Furthermore, additive interaction were observed between the As exposure and egg products intake, as well as bean products. Cd exposure also showed additive interactions with egg and bean products intake.
The consumption of eggs and bean products, as well as the levels of exposure to the heavy metals Cd and As, have been shown to have a substantial influence on cognitive impairment in the elderly population.
Alzheimer’s disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial ...etiology of AD, there is now more and more interest in nutraceutical agents with multiple effects such as Moringa oleifera (MO) that have strong anti-oxidative, anti-inflammatory, anticholinesterase, and neuroprotective virtues. In this study, we treated APP/PS1 mice with a methanolic extract of MO for four months and evaluated its effect on AD-related pathology in these mice using a multitude of behavioral, biochemical, and histochemical tests. Our data revealed that MO improved behavioral deficits such as anxiety-like behavior and hyperactivity and cognitive, learning, and memory impairments. MO treatment abrogated the Aβ burden to wild-type control mice levels via decreasing BACE1 and AEP and upregulating IDE, NEP, and LRP1 protein levels. Moreover, MO improved synaptic plasticity by improving the decreased GluN2B phosphorylation, the synapse-related proteins PSD95 and synapsin1 levels, the quantity and quality of dendritic spines, and neurodegeneration in the treated mice. MO is a nutraceutical agent with promising therapeutic potential that can be used in the management of AD and other neurodegenerative diseases.
Background
Accumulating evidence suggests that alterations in liver function may play an important role in the pathogenesis of Alzheimer’s disease (AD). However, it remains unclear whether there is ...any relationship between lower liver function and cognitive impairment among the elderly.
Methods
From 2017 to 2018, we recruited 7,201 older people (over 60 years old) from 51 community health centers in the Luohu District of Shenzhen City. According to the Mini-Mental State Examination (MMSE) score and education level, participants were divided into a cognitive impairment group (
n
= 372) and a normal cognitive function group (
n
= 6,829). Nonparametric test, chi-square tests, and binary logistic regression were used to analyze the data.
Results
Cognitive impairment group exhibits older age, more female sex, lower education level, and lower levels of albumin and triglyceride. Additionally, the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio was mainly distributed in the range of 1.17 to 1.3 in the cognitive impairment group, and 0.85 to 1.00 in the normal cognitive function group (
χ
2 = 10.02,
p
= 0.04). Binary logistic regression showed that cognitive impairment was significantly associated with age (
OR
= 0.934, 95%
CI
: 0.886–0.985,
p
= 0.017), female sex (
OR
= 2.255, 95%
CI
: 1.761–2.888,
p
< 0.001), lower education level (less than senior high school) (
OR
= 11.509, 95%
CI
: 9.064–14.613,
p
< 0.001), and lower albumin (
OR
= 1.023, 95%
CI
: 1.004–1.043,
p
= 0.011).
Conclusion
Except for age, female sex, and lower education level, lower level of albumin and elevated AST to ALT ratio correlate with cognitive impairment. Whether lower liver function plays a role in AD needs to be further studied.
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