Label-free autofluorescence and hyperspectral imaging of cerebral amyloid-ß lesions in aged squirrel monkeys.

The observation of amyloid-ß (Aß) lesions using autofluorescence in transgenic mice and human Alzheimer disease patients has been reported frequently. However, no reports verify the autofluorescence of spontaneous Aß amyloidosis in animals, to our knowledge. We validated the autofluorescence of Aß lesions in spontaneous squirrel monkey cases under label-free conditions; lesions had intense blue-white autofluorescence in fluorescence microscopy using excitation light at 400-440 nm. Thioflavin S staining and immunohistochemistry of the same specimens revealed that this blue-white autofluorescence was derived from Aß lesions. Hyperspectral analysis of these lesions revealed a characteristic spectrum with bimodal peaks at 440 and 460 nm, as reported for Aß lesions in mice. Principal component analysis using hyperspectral data specifically separated the Aß lesions from other autofluorescent substances, such as lipofuscin. A non-labeled and mechanistic detection of Aß lesions by hyperspectral imaging could provide valuable insights for developing early diagnostic techniques.

Targeting autophagy in Alzheimer's disease: Animal models and mechanisms.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss. Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta (Aß) and tau metabolism, and that autophagy dysfunction exacerbates amyloidosis and tau pathology. Therefore, targeting autophagy may be an effective approach for the treatment of AD. Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases. This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models. Finally, the opportunities, difficulties, and future directions of autophagy targeting in AD therapy are discussed.

Senile plaques and phosphorylated tau deposition in a super-aged rhesus monkey (Macaca mulatta).

The brain of a rhesus monkey that died at 43 years of age with symptoms of suspected cognitive dysfunction was analyzed. pathological analyses revealed characteristic Alzheimer's disease-related lesions: the aggregation of amyloid ß (Aß) in the form of senile plaques and phosphorylated tau proteins. We also revealed that Aß43, which is prone to aggregation and toxicity in humans, is involved in senile plaques in the brain of the rhesus monkey, as well as several other Aß species. Comparative studies of neuropathology using aged nonhuman primates lack behavioral descriptions compared to human medicine. This case report showed behavioral abnormalities and the detailed pathological changes that may have caused it in a super-aged rhesus monkey.

Whey protein powder with milk fat globule membrane attenuates Alzheimer's disease pathology in 3×Tg-AD mice by modulating neuroinflammation through the peroxisome proliferator-activated receptor γ signaling pathway.

Whey protein powder (PP), which is mainly derived from bovine milk, is rich in milk fat globule membrane (MFGM). The MGFM has been shown to play a role in promoting neuronal development and cognition in the infant brain. However, its role in Alzheimer's disease (AD) has not been elucidated. Here, we showed that the cognitive ability of 3×Tg-AD mice (a triple-transgenic mouse model of AD) could be improved by feeding PP to mice for 3 mo. In addition, PP ameliorated amyloid peptide deposition and tau hyperphosphorylation in the brains of AD mice. We found that PP could alleviate AD pathology by inhibiting neuroinflammation through the peroxisome proliferator-activated receptor γ (PPARγ)-nuclear factor-κB signaling pathway in the brains of AD mice. Our study revealed an unexpected role of PP in regulating the neuroinflammatory pathology of AD in a mouse model.

Oral administration of an integrative supplement (CogniCaps®) improves cognitive scores in aging dogs with canine cognitive dysfunction for at least two months: An open-label investigation in 10 dogs.

Background: Canine cognitive dysfunction (CCD), the dog analog of human Alzheimer's disease (AD), is a progressive neurodegenerative condition that presents many treatment challenges. There are few effective drugs with acceptable side effects for AD/CCD, which has prompted investigation into non-drug options, collectively termed nutraceuticals. Nutraceutical supplements are conceptually divided into conventional (Western) and non-conventional (Eastern) ingredients. Many of these individual supplements have shown in vitro and/or in vivo efficacy in ameliorating neuronal damage in rodent models, and some have demonstrated positive effects on cognition in rodent models and clinical trials in dogs and humans with cognitive impairment. Aim: The purpose of this open-label clinical trial was to investigate the effect of an oral integrative (combination of conventional nutraceuticals and Chinese herbals) supplement (CogniCaps®) on cognitive scores when administered to aging dogs with CCD over a 2-month period. Methods: Ten aging (>9-year-old) dogs with moderate (16-33) cognitive scores were recruited and administered oral CogniCaps® for two months. No additional drugs or nutraceuticals directed at improving cognitive function were allowed during the study period. Baseline cognitive scores were compared with those procured at 30 and 60 days. Cognitive scores for baseline, 30- and 60-days post-treatment were compared. Results: Cognitive scores improved at 30 days (38% reduction) and 60 days (41% reduction) post-treatment (p = 0.002). Scores did not differ between 30- and 60-day assessments (p = 0.7). Conclusion: The results of this small preliminary study suggest that the integrative supplement CogniCaps® might improve cognitive scores in dogs with CCD within the first 30 days of administration and that this improvement is sustained at 60-day follow up.

Can dolphins develop Alzheimer's disease?

Georgina Mills discusses research that raises the possibility of dementia in toothed dolphins.

Chitosan hydrogel nanoparticle enhance therapeutic effect of bovine umbilical mesenchymal stem cell conditioned medium on canine cognitive dysfunction or canine Alzheimer's like mediated by inhibition of neuronal apoptotic.

In treating brain diseases, such as canine cognitive dysfunction (CCD), most currently available potent drugs have weak therapeutic efficacy. One of the causes is the inability of the substance to reach the brain in therapeutic quantities. These pharmaceuticals lacked targeted mechanisms for drug delivery, coming about in an elevated drug concentration in imperative organs, which drove to drug harmfulness. In recent years, cell-free treatment (conditioned medium) determined from animal and human stem cells has provided new promise for treating brain diseases, as CM can stimulate the regeneration of neurons and prevent the inflammation and apoptotic of neurons caused by pathology or aging. On the other hand, it is well known that chitosan-hydrogel (CH) is a polymer derived from natural sources. It has been authorized for use in biomedical use because of its uncommon biodegradability, biocompatibility, and mucoadhesive properties. CH modification has been utilized to generate nanoparticles (NPs) for intranasal and intravenous brain targeting. NPs shown upgraded drug take-up to the brain with decreased side impacts due to their drawn out contact time with the nasal mucosa, surface charge, nanosize, and capacity to extend the tight intersections inside the mucosa. Due to the aforementioned distinctive characteristics, developing Chitosan Hydrogel Nanoparticles load with bovine umbilical mesenchymal stem cell conditioned medium is crucial as a new therapeutic strategy for CCD.

Animal models of Alzheimer's disease: Applications, evaluation, and perspectives.

Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer's disease (AD) have been made and multifarious novel therapeutic approaches have been developed, AD remains an incurable disease. Evidence shows that AD neuropathology occurs decades before clinical presentation. AD is divided into three stages: preclinical stage, mild cognitive impairment (MCI), and AD dementia. In the natural world, some animals, such as non-human primates (NHPs) and canines, can develop spontaneous AD-like dementia. However, most animals do not develop AD. With the development of transgenic techniques, both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods. Most AD research focuses on early-onset familial AD (FAD) because FAD is associated with specific genetic mutations. However, there are no well-established late-onset sporadic AD (SAD) animal models because SAD is not directly linked to any genetic mutation, and multiple environmental factors are involved. Moreover, the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages. This review summarizes the common models used to study AD, from yeast to NHP models, and discusses the different applications, evaluation methods, and challenges related to AD animal models, as well as prospects for the evolution of future studies.

Different Aß43 deposition patterns in the brains of aged dogs, sea lions, and cats.

Cerebral amyloid ß (Aß) deposition is a pathological hallmark of Alzheimer's disease (AD). There are several molecular species of Aß, including Aß40, Aß42, and Aß43, and the pathological roles of Aß43 have attracted particular attention in recent years. Aß43 is mainly deposited as senile plaques (SPs) in AD brains, and is known to be more amyloidogenic and neurotoxic than Aß42 and Aß40. Aß40 and Aß42 deposition have been demonstrated in several animal species, while Aß43 deposition has not been studied in animals. The brains of sea lions, dogs, and cats exhibit unique age-related Aß pathologies. In the present study, the deposition patterns of Aß40, Aß42, and Aß43 were examined immunohistochemically in the brains of aged dogs (n=52), sea lions (n=5), and cats (n=17). In dogs, most cerebral amyloid angiopathy (CAA) lesions and primitive SPs were positive for Aß42, Aß43, and Aß40. However, diffuse SPs and capillary CAA lesions were negative for Aß40. In sea lions, all SPs and most CAA lesions were positive for Aß42, Aß43, and Aß40, while capillary CAA lesions were negative for Aß40. In cats, Aß42-immunopositive granular aggregates and arteriole and capillary CAA lesions were positive for Aß43, but negative for Aß40. Double-labelling immunohistochemistry revealed the co-localization of Aß42 and Aß43. These findings suggest that Aß43 and Aß42 are frequently deposited in the brains of Carnivora animals and may play an important role in Aß pathology.

Autologous skin-derived neural precursor cell therapy reverses canine Alzheimer dementia-like syndrome in a proof of concept veterinary trial.

BACKGROUND: Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis. METHODS: A Phase 1/2A veterinary trial was conducted in N = 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippocampus using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses; these were compared to a brain bank (N = 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model (N = 16) was used to more closely evaluate intrahippocampal engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippocampal slice preparation. RESULTS: Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippocampus specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings: hippocampally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippocampus, neuronal differentiation in situ, and physiologically-correct integration into pyramidal layer circuits. CONCLUSIONS: With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippocampus.

Adult hippocampal neurogenesis and its impairment in Alzheimer's disease.

Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer's disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature on AHN and its impairments in AD.

Transcranial photobiomodulation (laser) therapy for cognitive impairment: A review of molecular mechanisms and potential application to canine cognitive dysfunction (CCD).

Alzheimer's disease (AD) is a common degenerative brain disorder of aging people which shares many clinical and pathological features with canine cognitive dysfunction (CCD). CCD is considered a naturally occurring model of human AD. Transcranial photobiomodulation therapy (tPBMT), also known as transcranial laser therapy, entails delivering photons of near infrared to infrared light from the skin surface of the scalp to the underlying brain. Specific molecular cellular receptors, called chromophores, absorb this energy, and use it to initiate biological reactions with potential therapeutic benefit. Improvement in cognitive ability using tPBMT has been documented in rodent AD models and human clinical trials. The purposes of this review are to provide an overview of the suspected molecular mechanisms of action of tPBMT for the treatment of cognitive decline and to propose potential application of this treatment modality for dogs affected by CCD.

Nutrients, Cognitive Function, and Brain Aging: What We Have Learned from Dogs.

Due to a difference in genetics, environmental factors, and nutrition, just like in people, dogs age at different rates. Brain aging in people and dogs share similar morphological changes including irreversible cortical atrophy, cerebral amyloid angiopathy, and ventricular enlargement. Due to severe and irreversible brain atrophy, some aging dogs develop cognitive dysfunction syndrome (CDS), which is equivalent to dementia or Alzheimer's disease (AD) in people. The risk factors and causes of CDS in dogs have not been fully investigated, but age, gender, oxidative stress, and deficiency of sex hormones appears to be associated with increased risk of accelerated brain aging and CDS in dogs. Both AD and CDS are incurable diseases at this moment, therefore more efforts should be focused on preventing or reducing brain atrophy and minimizing the risk of AD in people and CDS in dogs. Since brain atrophy leads to irreversible cognitive decline and dementia, an optimal nutritional solution should be able to not only enhance cognitive function during aging but also reduce irreversible brain atrophy. Up to now, only one nutritional intervention has demonstrated both cognition-enhancing benefits and atrophy-reducing benefits.

Cognitive Dysfunction in Cats: Update on Neuropathological and Behavioural Changes Plus Clinical Management.

Cognitive dysfunction syndrome (CDS) is an established condition in cats that shares many similarities with human Alzheimer's disease (AD), where cognitive decline ultimately results in dementia. Cats with CDS display behavioural abnormalities, including excessive Vocalisation, altered Interaction with owners (increased affection/attention), altered Sleep-wake cycles, House-soiling, Disorientation (spatial and/or temporal), alterations in Activity, Anxiety, and/or Learning/memory deficits (i.e., VISHDAAL). These cats develop neuropathologies, such as accumulation of ß-amyloid and hyperphosphorylated tau deposits. Because of its similarities to those in the brains of people with cognitive impairment and AD, the domestic cat could be a natural model for human dementia studies. It is important to diagnose CDS promptly in cats, ruling out other causes for these behavioural changes, to provide effective management. Interventions include environmental enrichment (e.g., easy access to key resources, calming pheromones), dietary supplementations (e.g., Senilife, Aktivait for cats, SAMe), specific diets (e.g., containing antioxidants, medium-chain triglycerides) and, potentially, medication (e.g., selegiline or propentofylline). This article reviews the literature about CDS in cats, its causes, neuropathology, clinical signs, diagnosis and potential management options. By doing so, it furthers our understanding of this condition and allows improved health, welfare and quality of life of affected cats.

TET2 Regulates the Neuroinflammatory Response in Microglia.

Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with LPS. We observed that microglia associated with amyloid ß plaques expressed TET2 in brain tissue from individuals with Alzheimer's disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders.

Dissecting Sholl Analysis into Its Functional Components.

Sholl analysis has been an important technique in dendritic anatomy for more than 60 years. The Sholl intersection profile is obtained by counting the number of dendritic branches at a given distance from the soma and is a key measure of dendritic complexity; it has applications from evaluating the changes in structure induced by pathologies to estimating the expected number of anatomical synaptic contacts. We find that the Sholl intersection profiles of most neurons can be reproduced from three basic, functional measures: the domain spanned by the dendritic arbor, the total length of the dendrite, and the angular distribution of how far dendritic segments deviate from a direct path to the soma (i.e., the root angle distribution). The first two measures are determined by axon location and hence microcircuit structure; the third arises from optimal wiring and represents a branching statistic estimating the need for conduction speed in a neuron.

Centella asiatica Protects d-Galactose/AlCl3 Mediated Alzheimer's Disease-Like Rats via PP2A/GSK-3ß Signaling Pathway in Their Hippocampus.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder more prevalent among the elderly population. AD is characterised clinically by a progressive decline in cognitive functions and pathologically by the presence of neurofibrillary tangles (NFTs), deposition of beta-amyloid (Aß) plaque and synaptic dysfunction in the brain. Centella asiatica (CA) is a valuable herb being used widely in African, Ayurvedic, and Chinese traditional medicine to reverse cognitive impairment and to enhance cognitive functions. This study aimed to evaluate the effectiveness of CA in preventing d-galactose/aluminium chloride (d-gal/AlCl3) induced AD-like pathologies and the underlying mechanisms of action were further investigated for the first time. Results showed that co-administration of CA to d-gal/AlCl3 induced AD-like rat models significantly increased the levels of protein phosphatase 2 (PP2A) and decreased the levels of glycogen synthase kinase-3 beta (GSK-3ß). It was further observed that, CA increased the expression of mRNA of Bcl-2, while there was minimal effect on the expression of caspase 3 mRNA. The results also showed that, CA prevented morphological aberrations in the connus ammonis 3 (CA 3) sub-region of the rat's hippocampus. The results clearly demonstrated for the first time that CA could alleviate d-gal/AlCl3 induced AD-like pathologies in rats via inhibition of hyperphosphorylated tau (P-tau) bio-synthetic proteins, anti-apoptosis and maintenance of cytoarchitecture.

Canine Cognitive Dysfunction: Pathophysiology, Diagnosis, and Treatment.

Canine cognitive dysfunction (CCD) is the canine analog of human Alzheimer disease (AD). The pathophysiology of CCD/AD is multifaceted. CCD is common in aged (>8 years) dogs, affecting between 14% and 35% of the pet dog population. Apparent confusion, anxiety, disturbance of the sleep/wake cycle, and decreased interaction with owners are all common clinical signs of CCD. Although there is no cure for CCD, several proven effective therapeutic approaches are available for improving cognitive ability and maintaining a good quality of life; instituting such therapies early in the disease course is likely to have the greatest positive clinical effect.

Astrocytic changes with aging and Alzheimer's disease-type pathology in chimpanzees.

Astrocytes are the main homeostatic cell of the central nervous system. In addition, astrocytes mediate an inflammatory response when reactive to injury or disease known as astrogliosis. Astrogliosis is marked by an increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Some degree of astrogliosis is associated with normal aging and degenerative conditions such as Alzheimer's disease (AD) and other dementing illnesses in humans. The recent observation of pathological markers of AD (amyloid plaques and neurofibrillary tangles) in aged chimpanzee brains provided an opportunity to examine the relationships among aging, AD-type pathology, and astrocyte activation in our closest living relatives. Stereologic methods were used to quantify GFAP-immunoreactive astrocyte density and soma volume in layers I, III, and V of the prefrontal and middle temporal cortex, as well as in hippocampal fields CA1 and CA3. We found that the patterns of astrocyte activation in the aged chimpanzee brain are distinct from humans. GFAP expression does not increase with age in chimpanzees, possibly indicative of lower oxidative stress loads. Similar to humans, chimpanzee layer I astrocytes in the prefrontal cortex are susceptible to AD-like changes. Both prefrontal cortex layer I and hippocampal astrocytes exhibit a high degree of astrogliosis that is positively correlated with accumulation of amyloid beta and tau proteins. However, unlike humans, chimpanzees do not display astrogliosis in other cortical layers. These results demonstrate a unique pattern of cortical aging in chimpanzees and suggest that inflammatory processes may differ between humans and chimpanzees in response to pathology.