Vascular risk factors and Alzheimer’s disease

Vascular factors are now established risk factors for cognitive decline, both for dementia and its two main subtypes: Alzheimer’s disease (AD) and vascular dementia. Their impact likely goes beyond causing an increase in concurrent vascular pathology, since they have been associated with increasing the risk of degenerative Alzheimer (plaque and tangle) pathology, either by increasing its rate of formation or reducing elimination from the brain, or a mixture of the two. A comprehensive series of reviews published in BMC Medicine, investigates the relationship between AD and cardiovascular diseases and risk factors from a clinical, pathological and therapeutic perspective. Whilst links between vascular factors and AD have clearly been demonstrated at both the clinical and pathological level, the nature of the relationship remains to be fully established and there is a lack of high quality treatment studies examining the extent to which vascular risk modification alters AD disease course. Further longitudinal mechanistic and therapeutic studies are required, especially to determine whether treatment of vascular risk can prevent or delay the onset of AD and/or reduce its rate of clinical progression.     

Parkinson’s disease and Alzheimer’s disease: a Mendelian randomization study

Background

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the top two common neurodegenerative diseases in elderly. Recent studies found the α-synuclein have a key role in AD. Although many clinical and pathological features between AD and PD are shared, the genetic association between them remains unclear, especially whether α-synuclein in PD genetically alters AD risk.

Results

We did not obtain any significant result (OR?=?0.918, 95% CI: 0.782–1.076, P?=?0.291) in MR analysis between PD and AD risk. In MR between α-synuclein in PD with AD risk, we only extracted rs356182 as the IV through a strict screening process. The result indicated a significant association based on IVW method (OR?=?0.638, 95% CI: 0.485–0.838, P?=?1.20E-03). In order to examine the robustness of the IVW method, we used other three complementary analytical methods and also obtained consistent results.

Conclusion

The overall PD genetic risk factors did not predict AD risk, but the α-synuclein susceptibility genetic variants in PD reduce the AD risk. We believe that our findings may help to understand the association between them, which may be useful for future genetic studies for both diseases.

     

Circadian and sleep dysfunction in Alzheimer’s disease

Alzheimer's disease (AD) is a devastating and irreversible cognitive impairment and the most common type of dementia. Along with progressive cognitive impairment, dysfunction of the circadian rhythms also plays a pivotal role in the progression of AD. A mutual relationship among circadian rhythms, sleep, and AD has been well-recommended. The etiopathogenesis of the disturbances of the circadian system and AD share some general features that also unlock the outlook of observing them as a mutually dependent pathway. Indeed, the burden of amyloid β (Aβ), neurofibrillary tangles (NFTs), neuroinflammation, oxidative stress, and dysfunction of circadian rhythms may lead to AD. Aging can alter both sleep timings and quality that can be strongly disrupted in AD. Increased production of Aβ and reduced Aβ clearance are caused by a close interplay of Aβ, sleep disturbance and raised wakefulness. Besides Aβ, the impact of tau pathology is possibly noteworthy to the sleep deprivation found in AD. Hence, this review is focused on the primary mechanistic complexities linked to disruption of circadian rhythms, sleep deprivation, and AD. Furthermore, this review also highlights the potential therapeutic strategies to abate AD pathogenesis.     

Why do Alzheimer’s disease and Parkinson’s disease target the same neurons?

The puzzle is to explain how cerebral involvement in the sporadic forms of Alzheimer’s disease (AD) and Parkinson’s disease (PD) can target the same population of vulnerable neurons. These neurons are poorly-myelinated projection neurons, lack of myelin being associated with high metabolic demand, high oxygen consumption, and high baseline oxidative stress. Yet the two diseases are clearly separable, with different intracellular markers, different risk factors, and different patterns of subcortical involvement.A theory is developed to show how two different pathophysiologies can preferentially affect the same neurons. In the case of AD, the hypothesis is as follows: the so-called vascular risk factors of AD, which include hypertension, diabetes, hyperlipidemia, and smoking, are all associated with increased systemic extracellular oxidative stress. High extracellular oxidative stress synergizes with high baseline intracellular oxidative stress to cause the disease. In the case of PD, mitochondrial failure associated with normal aging leads to diminished energy production and increased leakage of reactive oxygen species from mitochondria, a process which preferentially targets neurons with high baseline oxidative stress. In one case, the extra oxidative stress comes from outside the cell and, in the other case, it comes from inside the cell, i.e. from mitochondria. There is also evidence that neurofibrillary tangles are a protective mechanism against extracellular oxidative stress and that α-synuclein is a marker for mitochondrial failure. The basic pathophysiological difference is that AD is caused by oxidative stress alone, whereas PD is caused by oxidative stress plus failure of energy production.     

Neuroimaging biomarkers in Alzheimer’s disease and other dementias

In vivo imaging of β-amyloid (Aβ) has transformed the assessment of Aβ pathology and its changes over time, extending our insight into Aβ deposition in the brain by providing highly accurate, reliable, and reproducible quantitative statements of regional or global Aβ burden in the brain. This knowledge is essential for therapeutic trial recruitment and for the evaluation of anti-Aβ treatments. Although cross sectional evaluation of Aβ burden does not strongly correlate with cognitive impairment, it does correlate with cognitive (especially memory) decline and with a higher risk for conversion to AD in the aging population and MCI subjects. This suggests that Aβ deposition is a protracted pathological process starting well before the onset of symptoms. Longitudinal observations, coupled with different disease-specific biomarkers to assess potential downstream effects of Aβ are required to confirm this hypothesis and further elucidate the role of Aβ deposition in the course of Alzheimer’s disease.     

Transgenic Drosophila models of Alzheimer’s disease and tauopathies

Alzheimer’s disease (AD) is the most common form of senile dementia. Aggregation of the amyloid-β42 peptide (Aβ42) and tau proteins are pathological hallmarks in AD brains. Accumulating evidence suggests that Aβ42 plays a central role in the pathogenesis of AD, and tau acts downstream of Aβ42 as a modulator of the disease progression. Tau pathology is also observed in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and other related diseases, so called tauopathies. Although most cases are sporadic, genes associated with familial AD and FTDP-17 have been identified, which led to the development of transgenic animal models. Drosophila has been a powerful genetic model system used in many fields of biology, and recently emerges as a model for human neurodegenerative diseases. In this review, we will summarize key features of transgenic Drosophila models of AD and tauopathies and a number of insights into disease mechanisms as well as therapeutic implications gained from these models.     

Cystatin C in aging and in Alzheimer’s disease

Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer’s disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.     

APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease

Neuroinflammation is a central mechanism involved in neurodegeneration as observed in Alzheimer’s disease (AD), the most prevalent form of neurodegenerative disease. Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, directly influences disease onset and progression by interacting with the major pathological hallmarks of AD including amyloid-β plaques, neurofibrillary tau tangles, as well as neuroinflammation. Microglia and astrocytes, the two major immune cells in the brain, exist in an immune-vigilant state providing immunological defense as well as housekeeping functions that promote neuronal well-being. It is becoming increasingly evident that under disease conditions, these immune cells become progressively dysfunctional in regulating metabolic and immunoregulatory pathways, thereby promoting chronic inflammation-induced neurodegeneration. Here, we review and discuss how APOE and specifically APOE4 directly influences amyloid-β and tau pathology, and disrupts microglial as well as astroglial immunomodulating functions leading to chronic inflammation that contributes to neurodegeneration in AD.     

Study on Alzheimer’s disease model

Study on Alzheimer’s disease model     

Calcium hypothesis of Alzheimer’s disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca²⁺ signaling pathways responsible for cognition. Hydrolysis of the β-amyloid precursor protein (APP) yields two products that can influence Ca²⁺ signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca²⁺ that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca²⁺ within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca²⁺ being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca²⁺ signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca²⁺ signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca²⁺-dependent protein phosphatase calcineurin. The alteration in Ca²⁺ signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.     

Alzheimer’s disease,apolipoprotein E and hormone replacement therapy

Alzheimer’s disease is the most frequent cause of dementia in older patients. The prevalence is higher in women than in men. This may be the result of both the higher life expectancy of women and the loss of neuroprotective estrogen after menopause. Earlier age at menopause (spontaneous or surgical) is associated with an enhanced risk of developing Alzheimer’s disease. Therefore, it is postulated that estrogen could be protective against it. If so, increasing exposure to estrogen through the use of postmenopausal hormone replacement could also be protective against Alzheimer’s disease. The results of the clinical studies that have examined this hypothesis are inconclusive, however. One explanation for this is that estrogen treatment is protective only if it is initiated in the years immediately after menopause. Another possibility is that the neuroprotective effects of estrogen are negated by a particular genotype of apolipoprotein E. This protein plays an important role in cholesterol transport to the neurons. Studies that have examined the link between estrogen replacement therapy, Alzheimer’s disease and the E4 allele of ApoE are inconclusive. This article reviews the literature on the influence of hormone replacement therapy on the incidence and progression of Alzheimer’s disease.     

Selective neuronal vulnerability in Alzheimer’s disease

Alzheimer's disease (AD) is defined by a deficiency in specific behavioural and/or cognitive domains, pointing to selective vulnerabilities of specific neurons from different brain regions. These vulnerabilities can be compared across neuron subgroups to identify the most vulnerable neuronal types, regions, and time points for further investigation. Thus, the relevant organizational frameworks for brain subgroups will hold great values for a clear understanding of the progression in AD. Presently, the neuronal vulnerability has yet urgently required to be elucidated as not yet been clearly defined. It is suggested that cell-autonomous and non-cell-autonomous mechanisms can affect the neuronal vulnerability to stressors, and in turn modulates AD progression. This review examines cell-autonomous and non-cell-autonomous mechanisms that contribute to the neuronal vulnerability. Collectively, the cell-autonomous mechanisms seem to be the primary drivers responsible for initiating specific stressor-related neuronal vulnerability with pathological changes in certain brain areas, which then utilize non-cell-autonomous mechanisms and result in subsequent progression of AD. In summary, this article has provided a new perspective on the preventative and therapeutic options for AD.     

Is Alzheimer’s disease an inflammasomopathy?

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and, despite the tremendous efforts researchers have put into AD research, there are no effective options for prevention and treatment of the disease. The best way to reach this goal is to clarify the mechanisms involved in the onset and progression of AD. In the last few years the views about the drivers of AD have been changing and nowadays it is believed that neuroinflammation takes center stage in disease pathogenesis. Herein, we provide an overview about the role of neuroinflammation in AD describing the role of microglia and astroglia is this process. Then, we will debate the NLRP3 inflammasome putting the focus on its activation through the canonical, non-canonical and alternative pathways and the triggers involved herein namely endoplasmic reticulum stress, mitochondrial dysfunction, reactive oxygen species and amyloid β peptide. Data supporting the hypothesis that inflammasome-mediated peripheral inflammation may contribute to AD pathology will be presented. Finally, a brief discussion about the therapeutic potential of NLRP3 inflammasome modulation is also provided.     

O-GlcNAcylation and neuronal energy status: Implications for Alzheimer’s disease

Since the first clinical case reported more than 100 years ago, it has been a long and winding road to demystify the initial pathological events underling the onset of Alzheimer’s disease (AD). Fortunately, advanced imaging techniques extended the knowledge regarding AD origin, being well accepted that a decline in brain glucose metabolism occurs during the prodromal phases of AD and is aggravated with the progression of the disease. In this sense, in the last decades, the post-translational modification O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) has emerged as a potential causative link between hampered brain glucose metabolism and AD pathology. This is not surprising taking into account that this dynamic post-translational modification acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. Within this scenario, the present review aims to summarize the current understanding on the role of O-GlcNAcylation in neuronal physiology and AD pathology, emphasizing the close association of this post-translational modification with the emergence of AD-related hallmarks and its potential as a therapeutic target.     

β-amyloid oligomers and cellular prion protein in Alzheimer’s disease

Prefibrillar oligomers of the β-amyloid peptide (Aβ) are recognized as potential mediators of Alzheimer’s disease (AD) pathophysiology. Deficits in synaptic function, neurotoxicity, and the progression of AD have all been linked to the oligomeric Aβ assemblies rather than to Aβ monomers or to amyloid plaques. However, the molecular sites of Aβ oligomer action have remained largely unknown. Recently, the cellular prion protein (PrP^C) has been shown to act as a functional receptor for Aβ oligomers in brain slices. Because PrP^C serves as the substrate for Creutzfeldt–Jakob Disease (CJD), these data suggest mechanistic similarities between the two neurodegenerative diseases. Here, we review the importance of Aβ oligomers in AD, commonalities between AD and CJD, and the newly emergent role of PrP^C as a receptor for Aβ oligomers.