Translatability of Animal Models for Alzheimer's Disease Using a Machine Learning Based Workflow

Thermodynamic and kinetic origins of Alzheimer's and related diseases: A chemical engineer's perspective

Alzheimer’s disease is an incurable chronic neurodegenerative disorder and the leading cause of dementia, imposing a growing economic burden upon society. The disease progression is associated with gradual deposition of amyloid plaques and the formation of neurofibrillary tangles within the brain parenchyma, yet severe dementia is the culminating phase of the enduring pathology. Converging evidence suggests that Alzheimer’s disease-related cognitive decline is the outcome of an extremely complex and persistent pathophysiological process. The disease is characterized by distinctive abnormalities apparent at systemic, histological, macromolecular, and biochemical levels. Moreover, besides the well-defined and self-evident characteristic profuse neurofibrillary tangles, dystrophic neurites, and amyloid-beta deposits, the Alzheimer’s disease-associated pathology includes neuroinflammation, substantial neuronal loss, apoptosis, extensive DNA damage, considerable mitochondrial malfunction, compromised energy metabolism, and chronic oxidative stress. Likewise, distinctive metabolic dysfunction has been named a leading cause and a hallmark of Alzheimer’s disease that is apparent decades prior to disease manifestation. State-of-the-art metabolomics studies demonstrate that altered branched-chain amino acids (BCAAs) metabolism accompanies Alzheimer’s disease development. Lower plasma valine levels are correlated with accelerated cognitive decline, and, conversely, an increase in valine concentration is associated with reduced risk of Alzheimer’s disease. Additionally, a clear BCAAs-related metabolic signature has been identified in subjects with obesity, diabetes, and atherosclerosis. Also, arginine metabolism is dramatically altered in Alzheimer’s disease human brains and animal models. Accordingly, a potential role of the urea cycle in the Alzheimer’s disease development has been hypothesized, and preclinical studies utilizing intervention in the urea cycle and/or BCAAs metabolism have demonstrated clinical potential. Continual failures to offer a competent treatment strategy directed against amyloid-beta or Tau proteins-related lesions, which could face all challenges of the multifaceted Alzheimer’s disease pathology, led to the hypothesis that hyperphosphorylated Tau and deposited amyloid-beta proteins are just hallmarks or epiphenomena, but not the ultimate causes of Alzheimer’s disease. Therefore, approaches targeting amyloid-beta or Tau are not adequate to cure the disease. Accordingly, the modern scientific vision of Alzheimer’s disease etiology and pathogenesis must reach beyond the hallmarks, and look for alternative strategies and areas of research.

While the greatest risk factor for Alzheimer's disease (AD) is aging, women are disproportionately affected by the disease. Interestingly, the hippocampus and cerebellum exhibit gender-specific cytoarchitecture differences, which are associated with AD, despite the absence of a role in animal reproductive behavior or hormonal signaling. This study investigates the potential association of sex differences associated with AD by interrogating cerebellar and hippocampal volume in preclinical (MCI) as well as clinical phases of AD compared to cognitively normal patients (CN) and in an animal model of AD, the streptozotocin (STZ)-induced sporadic AD model. In order to investigate putative changes in cerebellum and hippocampus in a rat model of AD, we used a STZ-induced sporadic AD model at three different time points (2, 4, and 8 weeks) after surgery in male and female rats. Previous studies have reported hippocampal-dependent changes as well as sex-dependent behavioral and signaling effects in the STZ animal model of sporadic AD while our current study showed involvement of cerebellum-mediated changes. To interrogate the role of cerebellar volume in AD progression within the human context, we analyzed data available through the Alzheimer's Disease Neuroimaging Initiative (ADNI). In a cross-sectional analysis, we observed that levels of peripheral Glial Acidic Fibrillary Protein (GFAP) (astrocytic protein) were associated negatively with cerebellar and hippocampal volumes (β = -0.002, p-value = 0.04; β = -6.721, p-value < 0.0001) and were associated with sex specific differences in males. Our analysis identified that the effect on hippocampal volume was earlier in disease stage, reinforcing the relevance of longitudinal alterations of cerebellum and hippocampus volume over time. The STZ animal model of sporadic AD, corroborated the progressive changes in hippocampal volume and more minor and temporally delayed involvement of the cerebellum volume changes which were dependent on sex. This suggests that cerebellar involvement may be secondary to hippocampal neurodegeneration, and both regional differences were dependent on sex. Due to the association with GFAP, our findings may be due to network astrocyte connection spread regardless of primary pathology. Overall, our study uncovers a novel role for cerebellum in AD in a model and in the human context.

The current models unravel the molecular mechanisms underlying the intricate pathophysiology of Alzheimer's disease using zebrafish.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the progressive formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, inflammation, and impaired antioxidant systems. Early detection and intervention are vital for managing AD effectively. This review scrutinizes both in-vivo and in-vitro screening models employed in Alzheimer's disease research. in-vivo models, including transgenic mice expressing AD-related mutations, offer profound insights into disease progression and potential therapeutic targets. A thorough understanding of these models and mechanisms will facilitate the development of novel therapies and interventions for Alzheimer's disease. This review aims to provide an overview of the current experimental models in AD research, assess their strengths and weaknesses as model systems, and underscore the future prospects of experimental AD modeling. We conducted a systematic literature search across multiple databases, such as Pub- Med, Bentham Science, Elsevier, Springer Nature, Wiley, and Research Gate. The search strategy incorporated pertinent keywords related to Alzheimer's disease, in-vivo models, in-vitro models, and screening mechanisms. Inclusion criteria were established to identify studies focused on in-vivo and in-vitro screening models and their mechanisms in Alzheimer's disease research. Studies not meeting the predefined criteria were excluded from the review. A well-structured experimental animal model can yield significant insights into the neurobiology of AD, enhancing our comprehension of its pathogenesis and the potential for cutting-edge therapeutic strategies. Given the limited efficacy of current AD medications, there is a pressing need for the development of experimental models that can mimic the disease, particularly in pre-symptomatic stages, to investigate prevention and treatment approaches. To address this requirement, numerous experimental models replicating human AD pathology have been established, serving as invaluable tools for assessing potential treatments. In summary, this comprehensive review underscores the pivotal role of in-vivo and in-vitro screening models in advancing our understanding of Alzheimer's disease. These models offer invaluable insights into disease progression, pathological mechanisms, and potential therapeutic targets. By conducting a rigorous investigation and evaluation of these models and mechanisms, effective screening and treatment methods for Alzheimer's disease can be devised. The review also outlines future research directions and areas for enhancing AD screening models.

This paper focuses on the causation of diseases, particularly on the idea of a "genetic cause" taking Alzheimer's Disease (AD) as an example. We (1) provide some historical information and a synopsis of the current knowledge on the etiology and pathogenesis of AD, (2) analyse some conceptual problems related to the notion of "genetic disease", (3) elaborate on the alleged (genetic) cause of AD, and (4) place the discussion on the cause of AD in a broader philosophical context, paying attention to a constructivist perspective, the notions of causal connection and causal selection, and to some practical and normative consequences of our analysis. We conclude (a) that AD is not a specific disease entity with one specific cause, (b) that the idea of a single (sufficient) cause can still function as a heuristic tool in AD research and practice, and (c) that a "belief" in causation can go together with the notions of multicausality and probability.

Background and Objective: Alzheimer’s disease (AD) is a neurodegenerative disorder specified by deposition of b-amyloid (Ab) and neuronal loss that leads to learning and memory disturbances. One of the most important causes of AD is glutamate-dependent excitotoxicity in brain regions that is vulnerable to AD. According to previous reported results, it was revealed that riluzole, as a glutamate release inhibitor, could improve learning and memory in an experimental model of AD. The aim of this study was to determine the effects of riluzole on Hippocampal astrogliosis and amyloidosis in a rat model of AD. Materials and Methods: In the present study, the effects of riluzole administration at a dose of 10 mg/kg/day p.o. on hippocampal glial fibrillary acid protein (GFAP) as an astrogliosis marker and inducible nitric oxide synthase (iNOS) level in Ab (25-35)-injected rats was evaluated. Results: The results showed that in Ab (25–35)-injected rats, the intrahippocampal GFAP (p Conclusion: This study indicates that in rat model of AD, riluzole is able to attenuate NO synthesis with reducing hippocampal iNOS level, probably through inhibition of glutamatergic signaling pathway.

Proteomics in animal models of Alzheimer's and Parkinson's diseases

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Alzheimer's disease (AD) is an irredeemable chronic neurodegenerative disorder and the predominant cause of dementia. The disease progression is associated with the deposition of amyloid plaques and formation of neurofibrillary tangles in the brain, yet clinical dementia is the end and culminating stage of the enduring pathology. Recent evidence suggests that AD is characterized by distinctive abnormalities apparent on systemic, histological, macromolecular, and biochemical levels. Besides the well-described characteristic profuse neurofibrillary tangles, dystrophic neurites, and Aβ deposits, the AD pathology includes substantial neuronal loss, inflammation, extensive DNA damage, considerable mitochondrial malfunction, impaired energy metabolism, and chronic oxidative stress. Moreover, severe metabolic dysfunction leading to oxidative stress is a possible cause and hallmark of AD that is apparent decades before the disease manifestation. State-of-the-art metabolomics studies have proved that arginine and branched-chain amino acids metabolism disturbances accompany AD and contribute to its pathogenesis. Repetitive failures to find an efficient anti-amyloid or anti-Tau treatment, which would face the challenges of the complex AD pathology, led to the hypothesis that hyperphosphorylated Tau and deposited Aβ proteins are hallmarks, not the ultimate causes of AD. Accordingly, the modern scientific vision of AD etiology and pathogenesis must reach beyond the hallmarks and look for alternative strategies and areas of research.

Women are at higher risk for Alzheimer’s disease (AD) than men and hormonal changes during perimenopause are considered a risk factor. The relationship between ovarian hormones and AD has been explored using AD animal models, especially through ovariectomy (OVX) in established AD models. The link between early-stage AD and ovarian hormones, however, remains unclear, largely due to the lack of suitable animal models. Appropriate models for studying early-stage AD pathology, treatment, and prevention are critically needed. The App knock-in mouse model, which carries a single amyloid precursor protein (App) gene mutation, effectively reproduces early amyloid AD pathology. To elucidate the relationship between ovarian hormone deficiency and the behavioral phenotypes of a preclinical AD model, we applied a comprehensive behavioral test battery to this mouse model with bilateral OVX. The App mutation reduced anxiety-like behavior and impaired performance in the fear memory task. OVX restored the anxiety-like behavior of the App mutation mice to a level comparable to that in wild-type (WT) mice. Furthermore, OVX enhanced performance in a fear memory task in both genotypes and reduced amyloid-β staining in WT mice. Together, these findings suggest that OVX attenuates AD-related phenotypes in a preclinical AD model and in C57BL/6 J WT mice.

With the increasingly serious aging of the global population, dementia has already become a severe clinical challenge on a global scale. Dementia caused by Alzheimer's disease (AD) is the most common form of dementia observed in the elderly, but its pathogenetic mechanism has still not been fully elucidated. Furthermore, no effective treatment strategy has been developed to date, despite considerable efforts. This can be mainly attributed to the paucity of animal models of AD that are sufficiently similar to humans. Among the presently established animal models, non‐human primates share the closest relationship with humans, and their neural anatomy and neurobiology share highly similar characteristics with those of humans. Thus, there is no doubt that these play an irreplaceable role in AD research. Considering this, the present literature on non‐human primate models of AD was reviewed to provide a theoretical basis for future research.

Functional Neurobiology of Aging

The expression of histone deacetylase 6 (HDAC6)--a versatile enzyme with a known role in epigenetics--increases significantly in the hippocampus and other relevant brain regions in both patients with Alzheimer's disease (AD) and animal models of AD. However, when and how HDAC6 expression increases during the course of AD progression remains unclear. Whether HDAC6 overexpression is an underlying cause of AD or a condition resulting from AD is controversial. Mounting evidence suggests that increased HDAC6 expression contributes to AD-associated neurodegeneration, although beneficial effects have also been identified. This review article addresses recent research on HDAC6 structure and function, and highlights the potential detrimental and protective roles of HDAC6 overexpression in AD. We hope to shed light on whether HDAC6 overexpression is associated with AD etiopathogenesis or whether it rescues AD-associated neurodegeneration compensatorily. Furthermore, we discuss new evidence showing that HDAC6 may be a therapeutic target for AD.

A view of the origin and progression of Alzheimer's disease, AD, prevailing until now and formalized as the Amyloid Cascade Hypothesis theory, maintains that the disease is initiated by overproduction of beta-amyloid, Aβ, which is generated solely by the Aβ precursor protein, βAPP, proteolytic pathway and secreted from the cell. Consequent extracellular accumulation of Aβ triggers a cascade of molecular and cellular events leading to neurodegeneration that starts early in life, progresses as one prolonged process, builds up for decades, and culminates in symptomatic manifestations of the disease late in life. In this paradigm, a time window for commencement of therapeutic intervention is small and accessible only early in life. The outlook introduced in the present study is fundamentally different. It posits that the βAPP proteolytic/secretory pathway of Aβ production causes AD in humans no more than it does in either short- or long-lived non-human mammals that share this pathway with humans, accumulate beta-amyloid as they age, but do not develop the disease. Alzheimer's disease, according to this outlook, is driven by an additional powerful AD-specific pathway of Aβ production that operates in affected humans, is completely independent of the βAPP precursor, and is not available in non-human mammals. The role of the βAPP proteolytic pathway in the disease in humans is activation of this additional AD-specific Aβ production pathway. This occurs through accumulation of intracellular Aβ, primarily via ApoE-assisted cellular uptake of secreted beta-amyloid, but also through retention of a fraction of Aβ produced in the βAPP proteolytic pathway. With time, accumulated intracellular Aβ triggers mitochondrial dysfunction. In turn, cellular stresses associated with mitochondrial dysfunction, including ER stress, activate a second, AD-specific, Aβ production pathway: Asymmetric RNA-dependent βAPP mRNA amplification; animal βAPP mRNA is ineligible for this process. In this pathway, every conventionally produced βAPP mRNA molecule serves potentially as a template for production of severely 5'-truncated mRNA encoding not the βAPP but its C99 fragment (hence "asymmetric"), the immediate precursor of Aβ. Thus produced, N-terminal signal peptide-lacking C99 is processed not in the secretory pathway on the plasma membrane, but at the intracellular membrane sites, apparently in a neuron-specific manner. The resulting Aβ is, therefore, not secreted but is retained intraneuronally and accumulates rapidly within the cell. Increased levels of intracellular Aβ augment mitochondrial dysfunction, which, in turn, sustains the activity of the βAPP mRNA amplification pathway. These self-propagating mutual Aβ overproduction/mitochondrial dysfunction feedback cycles constitute a formidable two-stroke engine, an engine that drives Alzheimer's disease. The present outlook envisions Alzheimer's disorder as a two-stage disease. The first stage is a slow process of intracellular beta-amyloid accumulation. It results neither in significant neurodegenerative damage, nor in manifestation of the disease. The second stage commences with the activation of the βAPP mRNA amplification pathway shortly before symptomatic onset of the disease, sharply increases the rate of Aβ generation and the extent of its intraneuronal accumulation, produces significant damages, triggers AD symptoms, and is fast. In this paradigm, the time window of therapeutic intervention is wide open, and preventive treatment can be initiated any time, even late in life, prior to commencement of the second stage of the disease. Moreover, there are good reasons to believe that with a drug blocking the βAPP mRNA amplification pathway, it would be possible not only to preempt the disease but also to stop and to reverse it even when early AD symptoms have already manifested. There are numerous experimental models of AD, all based on a notion of the exceptionality of βAPP proteolytic/secretory pathway in Aβ production in the disease. However, with no drug even remotely effective in Alzheimer's disease, a long list of candidate drugs that succeeded remarkably in animal models, yet failed utterly in human clinical trials of potential AD drugs, attests to the inadequacy of currently employed AD models. The concept of a renewable supply of beta-amyloid, produced in the βAPP mRNA amplification pathway and retained intraneuronally in Alzheimer's disease, explains spectacular failures of both BACE inhibition and Aβ-immunotherapy in human clinical trials. This concept also forms the basis of a new generation of animal and cell-based experimental models of AD, described in the present study. These models incorporate Aβ- or C99-encoding mRNA amplification pathways of Aβ production, as well as intracellular retention of their product, and can support not only further investigation of molecular mechanisms of AD but also screening for and testing of candidate drugs aimed at therapeutic targets suggested by the present study.