Journal of Alzheimer's Disease - Volume 64, issue s1

Authors: Gutierrez, Antonia | Vitorica, Javier

Article Type: Research Article

Abstract: The continuing failure to develop an effective treatment for Alzheimer’s disease urges a better understanding of the pathogenic mechanisms and the improvement of current animal models to facilitate success for clinical interventions. The transgenic models have been so far designed to recapitulate one, or both, protein lesions found in the brain of patients, the extracellular amyloid plaques and the intraneuronal neurofibrillary tangles. However, in recent years, a third pathogenic component is gaining strength in the onset and progression of this disease, the neuroinflammatory response mediated primarily by the brain’s resident immune cells, microglia. This has been highlighted by the identification …of genes involved in innate immunity as risk factors to develop this neurodegenerative disease. Our current concept, mostly derived from amyloid-β producing models which show a robust microglial activation, supports an initial beneficial role of these glial cells followed by a pro-inflammatory cytotoxic function later on. This view is now challenged by emerging data in human postmortem samples. We have recently demonstrated that in the hippocampus of Braak V-VI individuals there is a prominent degenerative process of the microglial population, driven by phospho-tau, that might compromise neuronal homeostasis. This scenario of microglial dysfunction/degeneration should be taken into account for developing more reliable animal models of this disease and improve their predictive value for human drug efficacy testing. Finally, correcting dysregulated brain inflammatory responses might be a promising avenue to restore cognitive function. Show more

Keywords: Alzheimer’s disease, degeneration, inflammatory, innate immunity, microglia, transgenic models

DOI: 10.3233/JAD-179914

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S329-S338, 2018

Authors: Edison, Paul | Brooks, David J.

Article Type: Review Article

Abstract: Recent evidence suggests that neuroinflammation and immunity play a significant role in Alzheimer’s disease and other neurodegenerative diseases. It has also been observed that, independent of the presence of aggregated proteins, neuroinflammation could be present in different neurodegenerative diseases. It has also been suggested that neuroinflammation could occur well ahead of amyloid deposition in AD. Recent genetic studies and other preclinical studies specifically point to a role of neuroinflammation and, in this review, we evaluate the evidence of neuroinflammation in the Alzheimer’s disease trajectory and the different imaging modalities by which we could monitor neuroinflammation in vivo in humans.

Keywords: Alzheimer’s disease, astrocytes, microglia, neurodegeneration, neuroinflammation

DOI: 10.3233/JAD-179929

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S339-S351, 2018

Authors: Sahara, Naruhiko | Maeda, Jun | Ishikawa, Ai | Tokunaga, Masaki | Suhara, Tetsuya | Higuchi, Makoto

Article Type: Research Article

Abstract: Tauopathy is characterized by the fibrillar tau accumulation in neurons and glial cells. In order to advance our understanding of the causative mechanisms of tauopathy, neuroinflammation, which has been suggested to play important roles in disease progression, will require particular attention. Neuroinflammation is characterized predominantly by microglial activation. At present, it is still under debate whether microglial activation is a cause or a result of neurodegeneration. To search for a temporal relationship between neurodegeneration and neuroinflammation, our group demonstrated that in vivo imaging (e.g., tau-PET, TSPO-PET, and volumetric MRI) of tauopathy mice strongly supports the evidence of microglial activation …along with both pathological tau accumulation and brain atrophy. Both in vivo imaging and histochemical analysis confirmed that microglial TSPO accumulation was the late event during the pathogenesis of tauopathy. On the other hand, it is known that purinergic receptor P2Y12 as a marker of homeostatic microglia cells was reduced at an early stage of disease progression. In this review, we will introduce a phenotypic change of microglia in a mouse model of tauopathy and propose novel approaches to the establishment of imaging biomarkers, thereby targeting the early diagnosis of tauopathy. Show more

Keywords: Microglia, neuroinflammation, P2Y12 receptor, PET imaging, tauopathy, TSPO

DOI: 10.3233/JAD-179933

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S353-S359, 2018

Authors: McGeer, Patrick L. | McGeer, Edith

Article Type: Research Article

Abstract: The means are now at hand to conquer Alzheimer’s disease (AD). The method is to identify those at risk for the disease before clinical signs develop. That is followed by implementing measures that can effectively prevent disease development. Since biotechnology markers have shown that AD commences at least a decade before cognitive deficits set in, there is an extended window of opportunity to successfully prevent disease development. Methods of identifying those at risk include positron electron microscopy for AD senile plaques, blood or saliva analysis for elevation of the amyloid-β protein fragment terminating at position 42, and cerebrospinal fluid analysis …showing a decrease in content of this protein. Of the modalities available, saliva is by far the simplest and least invasive. Once identified, those at risk can prevent disease development through self treatment by consumption of non-steroidal anti-inflammatory drugs, adhering to a Mediterranean diet, and consuming antioxidants such as quercitin which is contained in coffee. Show more

Keywords: Aβ42 , coffee, Mediterranean diet, non-steroidal anti-inflammatory drugs, saliva

DOI: 10.3233/JAD-179913

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S361-S363, 2018

Authors: Martini, Alessandra C. | Forner, Stefania | Trujillo-Estrada, Laura | Baglietto-Vargas, David | LaFerla, Frank M.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease.

Keywords: 3xTg-AD, amyloid-β, animal models, comorbidities, inflammation, stem cell therapy, synaptic loss, tau

DOI: 10.3233/JAD-179917

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S365-S378, 2018

Authors: Lane, Darius J.R. | Ayton, Scott | Bush, Ashley I.

Article Type: Review Article

Abstract: Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron’s biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This “Janus-faced” nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the …metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer’s disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves “ferroptosis”, a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, apoptosis, astrocytes, ferroptosis, iron, lipid peroxidation, oxidative stress, neuroinflammation

DOI: 10.3233/JAD-179944

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S379-S395, 2018

Authors: Mecocci, Patrizia | Baroni, Marta | Senin, Umberto | Boccardi, Virginia

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) represents the most common form of dementia in old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved. The definition of AD has changed over the past years, offering an ever more detailed definition of pre-morbid and pre-clinical status, but without a similar strong emphasis on the role of aging as the main risk factor. In fact, while early-onset AD is a clear consequence of gene mutations, late-onset AD is more likely due to a gradual accumulation of age-related damages. The pathogenetic amyloid cascade hypothesis has been recently questioned due to multiple clinical …failures. Furthermore, several studies reported that cognitively normal elderly have a high amyloid deposition in the brain comparable to the levels observed in old age subjects with AD. This suggests that amyloid accumulation enters into the normal process of aging and what really triggers neuronal death and clinical manifestation in late-onset AD still needs further explanation. In this context, ‘normal brain aging’ and AD might represent a different pathway of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes affecting the brain may be considered as biologic manifestations of increasing entropy. Bioenergetic deficits due to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. So, increased amyloid in the brain of old age subjects may represent the downstream event expression of a biological system that is cooling down because of its exhaustion and not the core causative factor of late-onset dementia. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, energy, entropy, mitochondria, old age

DOI: 10.3233/JAD-179903

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S397-S404, 2018

Authors: Clarke, Julia R. | Ribeiro, Felipe C. | Frozza, Rudimar L. | De Felice, Fernanda G. | Lourenco, Mychael V.

Article Type: Review Article

Abstract: Clinical trials have extensively failed to find effective treatments for Alzheimer’s disease (AD) so far. Even after decades of AD research, there are still limited options for treating dementia. Mounting evidence has indicated that AD patients develop central and peripheral metabolic dysfunction, and the underpinnings of such events have recently begun to emerge. Basic and preclinical studies have unveiled key pathophysiological mechanisms that include aberrant brain stress signaling, inflammation, and impaired insulin sensitivity. These findings are in accordance with clinical and neuropathological data suggesting that AD patients undergo central and peripheral metabolic deregulation. Here, we review recent basic and clinical …findings indicating that metabolic defects are central to AD pathophysiology. We further propose a view for future therapeutics that incorporates metabolic defects as a core feature of AD pathogenesis. This approach could improve disease understanding and therapy development through drug repurposing and/or identification of novel metabolic targets. Show more

Keywords: Alzheimer’s disease, hormones, memory, metabolism, therapy

DOI: 10.3233/JAD-179911

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S405-S426, 2018

Authors: Lee, Jung Hyun | Jahrling, Jordan B. | Denner, Larry | Dineley, Kelly T.

Article Type: Review Article

Abstract: Insulin resistance can occur when the body is unable to respond to insulin even in excess. In the brain, insulin manages glucose metabolism in regions such as the hippocampus and plays a key role in directly regulating ERK, a kinase required for the type of memory compromised in early Alzheimer’s disease (AD). Human imaging studies show that brain glucose utilization declines with age and is notably impaired in subjects with early AD. Likewise, animal models of AD or insulin resistance, or both, demonstrate that dysfunctional insulin signaling and insulin resistance in the brain have reciprocity with neuroinflammation and aberrant accumulation …of amyloid-β (Aβ), pathological hallmarks in AD. As such, the association between brain insulin activity and AD has led to clinical trials testing the efficacy of insulin and insulin-sensitizing drugs to intervene in AD. Based on recent inquiries to ClinicalTrials.gov, we evaluated thirty-three clinical studies related to AD and insulin. The search filtered for interventional clinical trials to test FDA-approved drugs or substances that impinge upon the insulin signaling pathway. Insulin, metformin, and thiazolidinediones were the three main interventions assessed. Overall, these strategies are expected to negate the effects of brain insulin resistance by targeting insulin signaling pathways involved in neuroinflammation, metabolic homeostasis, synaptic functional and structural integrity. The goal of this review is to provide an update on insulin and ERK signaling in relation to memory, its decline in early AD, and provide an overview of clinical trials related to insulin for early AD intervention. Show more

Keywords: Alzheimer’s disease, animal model, clinical trials, ERK, insulin resistance, learning and memory, metabolism, mitochondria, PPARγ

DOI: 10.3233/JAD-179923

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S427-S453, 2018

Authors: Stockburger, Carola | Eckert, Schamim | Eckert, Gunter P. | Friedland, Kristina | Müller, Walter E.

Article Type: Review Article

Abstract: Because of the failure of all amyloid-β directed treatment strategies for Alzheimer’s disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development. To overcome these problems, we used a …top-down approach by investigating several older antidementia drugs with clinical evidence of therapeutic efficacy. These include EGb761® (standardized ginkgo biloba extract), piracetam, and Dimebon. All improve experimentally many aspects of mitochondrial dysfunction including mitochondrial dynamics and also improve cognition and impaired neuronal plasticity, the functionally most relevant consequences of mitochondrial dysfunction. All partially inhibit opening events of the mitochondrial permeability transition pore (mPTP) which previously has mainly been discussed as a mechanism relevant for the induction of apoptosis. However, as more recent work suggests the mPTP as a master regulator of many mitochondrial functions, our data suggest the mPTP as a possible relevant drug target within the love triangle between mPTP regulation, mitochondrial dynamics, and mitochondrial function including regulation of neuronal plasticity. Drugs interfering with mPTP function will improve not only mitochondrial impairment in aging and AD but also will have beneficial effects on impaired neuronal plasticity, the pathomechanism which correlates best with functional deficits (cognition, behavior) in aging and AD. Show more

Keywords: Antidementia drugs, inhibition of mitochondrial permeability transition pore function, mitochondrial dysfunction, therapeutic efficacy

DOI: 10.3233/JAD-179915

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S455-S467, 2018