Rodent Models Of Alzheimer's Disease Research Articles

Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice.

Age-related neurodegenerative diseases (NDDs) are associated with the aggregation and propagation of specific pathogenic protein species (e.g., Aβ, α-synuclein). However, whether disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation, with its frequent outcome of random protein misfolding, is sufficient to recapitulate many early features of NDDs, including perturbed Ca2+ signaling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in behavioral changes reminiscent of early Alzheimer disease (AD), such as learning and memory deficits, maladaptive emotional responses, epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation, accompanied by hippocampal NPY expression and cerebral glucose hypometabolism. Collectively, our findings suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs, providing an alternative framework for understanding the initiation of AD.

Evaluation of Styrylbenzene analog- FSB and its affinity to bind parenchymal plaques and tangles in patients of Alzheimer's disease.

Although several histochemical markers for senile plaques (SP) and neurofibrillary tangles (NFTs) have been synthesized since the discovery of plaques in Alzheimer's disease (AD), only a handful of these markers stain both lesions in the human brain. Despite discovery of its ability to stain both SP and NFT over 13years ago, the styrylbenzene derivative, (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), has only recently gained attention, primarily due to its ability to function as a contrasting agent for MRI imaging of AD pathology in vivo. The structure of the compound is a nuclide with quantized angular momentum, which explains its value as a contrast agent. In the current study, modification of the established staining procedure produced meaningful improvement in the labeling of plaques and tangles in the human brain. We utilized two rodent models of AD to show FSB's value in labeling both Aβ and tau lesions. Furthermore, our current modification allows us to detect SP in rodent brains in 15min and both SP and NFT in human brains within 20min. The study presents new evidence regarding potential binding targets for FSB as well as optimization protocols in which various parameters have been manipulated to show how section thickness, use of frozen versus paraffin-embedded sections, and selection of staining media can affect the intensity of the plaque and tangle staining in the brain. To determine the target FSB potentially binds, we performed double immunolabeling of FSB with mOC64 (a conformational antibody that label Aβ1-42). Results indicated that all plaques in the brain colocalized with mOC64, suggesting that FSB has the potential to bind all Aβ containing plaques, making it a very sensitive detector of multiple forms of SP... All antibodies were assessed for the degree of colocalization with FSB in order to better understand potential binding targets. We found more than 90% hyperphosphorylated Tau against AT8, AT180 and S214 colocalized with FSB labeled tangles. On the other hand, more than 90% of the mOC64 containing plaques colocalized with FSB stained plaques. Our results indicate that FSB is a valuable marker that can be used to detect AD pathologies in human and rodent brains with greater fluorescence intensity relative to other conventional fluorescence markers.

Suppression of hippocampal GABAergic transmission impairs memory in rodent models of Alzheimer's disease

Emerging evidence demonstrates the potential involvement of hippocampal GABAergic transmission in the process of memory acquisition and consolidation, while no consistent report is available to address the adaptation of hippocampal GABAergic transmission and its contribution to memory deficiency in the setting of Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF) is a key molecule that regulates GABAergic transmission. In the brain, mature BDNF is generated from the proteolytic cleavage of proBDNF, while BDNF and proBDNF have differential effects on central GABAergic transmission. First, the present study reports a remarkable increase of proBDNF/BNDF ratio in the hippocampal CA1 area in rodent models of AD, indicating a potential impaired process of BDNF maturation from proBDNF cleavage. We report a suppressed hippocampal GABAergic strength, potentially resulting from the reduced expression of anion chloride co-transporter KCC2 and subsequent positive shift of GABAergic Cl-equilibrium potential (ECl-), which is attenuated by microinjection of BDNF with proBDNF inhibitor TAT-Pep5. We also show that normalization of proBDNF/BDNF signaling or GABAergic ECl-by intracerebroventricular (i.c.v.) administration of bumetanide remarkably improves the cognitive performance in Morris water maze test and fear conditioning test in rodent models of AD. These results demonstrate a critical role of hippocampal proBDNF/BDNF in regulating GABAergic transmission and contributing to memory dysfunction in rodent models of 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.

The Effects of Physical Running on Dendritic Spines and Amyloid-beta Pathology in 3xTg-AD Male Mice.

Memory loss is the key symptom of Alzheimer's disease (AD). As successful drug treatments have not yet been identified, non-pharmaceutical interventions such as physical exercise and training have been employed to improve the memory function of people with dementia. We investigated the effect of prolonged physical running on hippocampal-dependent spatial memory and its underlying mechanisms using a well-established rodent model of AD. 3xTg-AD transgenic mice and non-transgenic mice were subjected to voluntary wheel running for 5 months (1 hour per day, 5 days per week), followed by spatial memory testing. After the behavioral testing, dendritic spines, synapses, and synaptic proteins as well as amyloid-beta (Aβ) pathology were analyzed in the dorsal hippocampi. Running improved hippocampal-dependent spatial memory in 3xTg-AD mice. This running strategy prevented both thin and mushroom-type spines on CA1 pyramidal cells in 3xTg-AD mice, whereas the effects of running in non-transgenic mice were limited to thin spines. The enormous effects of running on spines were accompanied by an increased number of synapses and upregulated expression of synaptic proteins. Notably, running downregulated the processing of amyloid precursor protein, decreasing intracellular APP expression and extracellular Aβ accumulation, and spatial memory performance correlated with levels of Aβ peptides Aβ1-40 and Aβ1-42. These data suggest that prolonged running may improve memory in preclinical AD via slowing down the amyloid pathology and preventing the loss of synaptic contacts.

The offspring of mothers harboring APP/PS1 mutations presents early changes in memory and brain metabolism.

Previous studies suggested that individuals with a maternal history of Alzheimer's Disease (AD) are at higher risk of developing AD than individuals with a paternal history of AD. One could suggest that intra-uterine interactions might be responsible for elevating this risk. In this context, AD rodent models are highly suited for improving our understanding of this matter since animals reach adulthood in a few months. Here, we aimed at investigating changes in memory-related processes and brain metabolism on the offspring born to transgenic mothers harboring human APP/PS1 mutations. We hypothesized that offspring born to AD-transgenic mothers will present early memory and brain glucose metabolism changes. Rats born to F344-AD (Tg-AD) mothers and wild-type fathers (WT), the maternal AD group, and rats born to WT mothers and Tg-AD fathers, the paternal AD group, were evaluated in two different time-points: ∼5.5, and ∼9.5 months. To assess spatial working memory, spontaneous alternation behavior was evaluated in the Y-maze test. Furthermore, micro-PET [18 F]FDG was used to assess brain glucose metabolism (SUVr normalization, pons as reference region). Y-maze test demonstrated that rats born to transgenic mothers presented memory disturbances, indexed by spontaneous alternation, at ∼5.5 months (p = 0.0028, Figure 1A) and ∼9.5 months (p = 0.0062, Figure 1B), while rats born to WT mothers and Tg-AD fathers exhibited a decline in spontaneous alternation only at ∼9.5 months (p = 0.0181, Figure 1B). No changes were found in brain glucose metabolism at ∼5.5 months for both groups. However, rats born to AD-Tg mothers present brain glucose hypermetabolism at ∼9,5 months. Our findings demonstrate that rats born to AD-Tg mothers harboring APP/PS1 mutations present cognitive decline and brain glucose metabolism abnormalities earlier than those born to WT mothers. Further studies are needed to understand the biological basis behind this phenomenon.

Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases.

The blood brain barrier (BBB) is an obstacle for the delivery of potential molecular therapies for neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Although there has been a proliferation of potential disease modifying therapies for these progressive conditions, strategies to deliver these large agents remain limited. High intensity MRI guided focused ultrasound has already been FDA approved to lesion brain targets to treat movement disorders, while lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the BBB. Pre-clinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of AD and PD. Recent small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI guided BBB opening is used to enhance the delivery of newly developed molecular therapies.

Neuroprotective Potential of Mung Bean (Vigna radiata L.) Polyphenols in Alzheimer's Disease: A Review.

Mung bean contains various neuroprotective polyphenols, so it might be a healthy food for Alzheimer's disease (AD) prevention. Totally, 19 major phenolic compounds were quantified in mung bean, including 10 phenolic acids and 9 flavonoids. After summarizing their contents and effective doses in rodent AD models, it was speculated that vitexin, isovitexin, sinapic acid, and ferulic acid might be the major bioactive compounds for mung bean-mediated neuroprotection. The mechanisms involved inhibition of β-amyloidogenesis, tau hyperphosphorylation, oxidative stress, and neuroinflammation, and promotion of autophagy and acetylcholinesterase enzyme activity. Notably, the neuroprotective phenolic profile in mung bean changed after germination, with decreased vitexin and isovitexin, and increased rutin, isoquercitrin, isorhamnetin, and caffeic acid detected. However, only studies of individual phenolic compounds in mung bean are published at present. Hence, further studies are needed to elucidate the neuroprotective activities and mechanisms of extractions of mung bean seeds and sprouts, and the synergism between different phenolic compounds.

Protective Effects of Nicotinamide Adenine Dinucleotide and Related Precursors in Alzheimer's Disease: A Systematic Review of Preclinical Studies.

Data from preclinical studies propose nicotinamide adenine dinucleotide (NAD+) as a neuroprotective and bioenergetics stimulant agent to treat Alzheimer's disease (AD); however, there seems to be inconsistency between behavioral and molecular outcomes. We performed this systematic review to provide a better understanding of the effects of NAD+ in rodent AD models and to summarize the literature.Studies were identified by searching PubMed, EMBASE, Scopus, Google Scholar, and the reference lists of relevant review articles published through December 2020. The search strategy was restricted to articles about NAD+, its derivatives, and their association with cognitive function in AD rodent models. The initial search yielded 320 articles, of which 11 publications were included in our systematic review.Based on the primary outcomes, it was revealed that NAD+ improves learning and memory. The secondary endpoints also showed neuroprotective effects of NAD+ on different AD models. The proposed neuroprotective mechanisms included, but were not limited to, the attenuation of the oxidative stress, inflammation, and apoptosis, while enhancing the mitochondrial function.The current systematic review summarizes the preclinical studies on NAD+ precursors and provides evidence favoring the pro-cognitive effects of such components in rodent models of AD.

Adult Hippocampal Neurogenesis in Aging and Alzheimer's Disease.

Cognitive deficits associated with Alzheimer's disease (AD) severely impact daily life for the millions of affected individuals. Progressive memory impairment in AD patients is associated with degeneration of the hippocampus. The dentate gyrus of the hippocampus, a region critical for learning and memory functions, is a site of adult neurogenesis in mammals. Recent evidence in humans indicates that hippocampal neurogenesis likely persists throughout life, but declines with age and is strikingly impaired in AD. Our understanding of how neurogenesis supports learning and memory in healthy adults is only beginning to emerge. The extent to which decreased neurogenesis contributes to cognitive decline in aging and AD remains poorly understood. However, studies in rodent models of AD and other neurodegenerative diseases raise the possibility that targeting neurogenesis may ameliorate cognitive dysfunction in AD. Here, we review recent progress in understanding how adult neurogenesis is impacted in the context of aging and AD.

L-3-n-Butylphthalide Effectively Improves the Glymphatic Clearance and Reduce Amyloid-β Deposition in Alzheimer's Transgenic Mice.

Amyloid-β (Aβ) deposit in the parenchyma is a major characteristic in Alzheimer's disease (AD), and the impaired glymphatic clearance contributes to the Aβ accumulation. It was reported that L-3-n-butylphthalide (NBP) showed the potential neuroprotective effect in the rodent models of AD. The effects of NBP on the glymphatic system were explored in this study. In the wild-type mice, both CSF tracer influx and perivascular drainage increased after NBP treatment compared with vehicle treatment. Moreover, NBP promoted the perivascular drainage of Aβ via increased cerebral pulsation, which could be inhibited by propranolol. Then, we studied the potential of 3-month NBP treatment on Aβ deposits in 8-month-old APP/PS1 transgenic mice. NBP daily treatments remarkably improved cognitive behavior in Morris water maze. Furthermore, NBP could reduce Aβ deposition and decrease parenchymal Aβ levels. In addition, NBP markedly improved the perivascular AQP4 localization. Our results indicated that NBP could enhance the glymphatic clearance and reduce parenchymal Aβ deposit in the APP/PS1 mice, suggesting that it may have potential in the treatment of AD.

Sowing the Seeds of Discovery: Tau-Propagation Models of Alzheimer's Disease.

The propagation of pathological proteins throughout the brain is the primary physiological hallmark of the progression of Alzheimer's Disease (AD). A growing body of evidence indicates that hyperphosphorylated Tau proteins are spread transcellularly between neurons in a prionlike fashion, inducing misfolding and aggregation into neurofibrillary tangles which accumulate along specific connectivity pathways. Earlier transgenic rodent AD models did not capture this disease-relevant spread, and therefore, seeded Tau-propagation models have been developed. Here, mutant human Tau (as isolated protein or packaged into an adeno-associated virus (AAV) viral vector) is stereotaxically injected into select brain regions and its histopathological propagation to downstream neurons quantified. These models offer a faster and more direct mechanism to evaluate genetic components and therapeutic approaches which attenuate Tau spreading in vivo. Recently, these Tau-seeding models have revealed several new targets for AD drug discovery, including nSMase2, SIRT1, p300/CBP, LRP1, and TYROBP, as well as the potential therapeutics based on melatonin and chondroitinase ABC. Importantly, these Tau-propagation rodent models more closely phenocopy the progression of AD in humans and are therefore likely to improve preclinical studies and derisk future moves into clinical trials.

Alterations in odor hedonics in the 5XFAD Alzheimer’s disease mouse model and the influence of sex.

Olfactory impairments, including deficits in odor detection, discrimination, recognition, and changes in odor hedonics, are reported in the early stages of Alzheimer's disease (AD). Rodent models of AD display deficits in odor learning, detection, and discrimination-recapitulating the clinical condition. However, the impact of familial AD genetic mutations on odor hedonics is unknown. We tested 2-, 4-, and 6-month-old 5XFAD (Tg6799) mice in the 5-port odor multiple-choice task designed to assay a variety of odor-guided behaviors, including odor preferences/hedonics. We found that 5XFAD mice investigated odors longer than controls, an effect that was driven by 6-month-old mice. Interestingly, this effect was carried by females in the 5XFAD group, who investigated odors longer than age-matched males. Upon examining behavior directed toward individual odors to test for aberrant odor preferences, we uncovered that 5XFAD females at several ages displayed heightened preferences toward some of the odors, indicating aberrant hedonics. We observed no impairments in the ability to engage in the task in 5XFAD mice. Taken together, 5XFAD mice, particularly 5XFAD females, displayed prolonged odor investigation behavior and enhanced preferences to certain odors. The data provide insight into hedonic alterations that may occur in AD mouse models and how these are influenced by biological sex. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Challenges and Opportunities of Deferoxamine Delivery for Treatment of Alzheimer’s Disease, Parkinson’s Disease, and Intracerebral Hemorrhage

Deferoxamine mesylate (DFO) is an FDA-approved, hexadentate iron chelator routinely used to alleviate systemic iron burden in thalassemia major and sickle cell patients. Iron accumulation in these disease states results from the repeated blood transfusions required to manage these conditions. Iron accumulation has also been implicated in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), and secondary injury following intracerebral hemorrhage (ICH). Chelation of brain iron is thus a promising therapeutic strategy for improving behavioral outcomes and slowing neurodegeneration in the aforementioned disease states, though the effectiveness of DFO treatment is limited on several accounts. Systemically administered DFO results in nonspecific toxicity at high doses, and the drug's short half-life leads to low patient compliance. Mixed reports of DFO's ability to cross the blood-brain barrier (BBB) also appear in literature. These limitations necessitate novel DFO formulations prior to the drug's widespread use in managing neurodegeneration. Herein, we discuss the various dosing regimens and formulations employed in intranasal (IN) or systemic DFO treatment, as well as the physiological and behavioral outcomes observed in animal models of AD, PD, and ICH. The clinical progress of chelation therapy with DFO in managing neurodegeneration is also evaluated. Finally, the elimination of intranasally administered particles via the glymphatic system and efflux transporters is discussed. Abundant preclinical evidence suggests that intranasal DFO treatment improves memory retention and behavioral outcome in rodent models of AD, PD, and ICH. Several other biochemical and physiological metrics, such as tau phosphorylation, the survival of tyrosine hydroxylase-positive neurons, and infarct volume, are also positively affected by intranasal DFO treatment. However, dosing regimens are inconsistent across studies, and little is known about brain DFO concentration following treatment. Systemic DFO treatment yields similar results, and some complex formulations have been developed to improve permeability across the BBB. However, despite the success in preclinical models, clinical translation is limited with most clinical evidence investigating DFO treatment in ICH patients, where high-dose treatment has proven dangerous and dosing regimens are not consistent across studies. DFO is a strong drug candidate for managing neurodegeneration in the aging population, but before it can be routinely implemented as a therapeutic agent, dosing regimens must be standardized, and brain DFO content following drug administration must be understood and controlled via novel formulations.

Modification of methods to use Congo-red stain to simultaneously visualize amyloid plaques and tangles in human and rodent brain tissue sections.

Although there are multiple histochemical tracers available to label plaques and tangles in the brain to evaluate neuropathology in Alzheimer disease (AD), few of them are versatile in nature and compatible with immunohistochemical procedures. Congo Red (CR) is an anisotropic organic stain discovered to label amyloid beta (Aβ) plaques in the brain. Unfortunately, its use is underappreciated due to its low resolution and brightness as stated in previous studies using bright field microscopy. Here, we modified a previous method to localize both plaques and tangles in brains from humans and a transgenic rodent model of AD for fluorescence microscopic visualization. The plaque staining affinities displayed by CR were compared with fibrillar pattern labeling seen with Thioflavin S. This study summarizes the optimization of protocols in which various parameters have been finetuned. To determine the target CR potentially binds, we have performed double labeling with different antibodies against Aβ as well as phosphorylated Tau. The plaque staining affinities exhibited by CR are compared with those associated with the diffuse pattern of labeling seen with antibodies directed against different epitopes of Aβ. Neither CP13, TNT2 or TOC1 binds all the neurofibrillary tangles as revealed by CR labeling in the human brain. Additionally, we also evaluated double labeling with AT8, AT180, and PHF1. Interestingly, PHF-1 shows 40% colocalization and AT8 shows 15% colocalization with NFT. Thus, CR is a much better marker to detect AD pathologies in human and rodent brains with higher fluorescence intensity relative to other conventional fluorescence markers.

Age-Specific Retinal and Cerebral Immunodetection of Amyloid-β Plaques and Oligomers in a Rodent Model of Alzheimer's Disease.

Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer's disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature. This study's aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in the retina of a rodent model of AD. Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies. We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway. Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye.

Alzheimer's Disease: The Link Between Amyloid-β and Neurovascular Dysfunction.

While prevailing evidence supports that the amyloid cascade hypothesis is a key component of Alzheimer's disease (AD) pathology, many recent studies indicate that the vascular system is also a major contributor to disease progression. Vascular dysfunction and reduced cerebral blood flow (CBF) occur prior to the accumulation and aggregation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Although research has predominantly focused on the cellular processes involved with Aβ-mediated neurodegeneration, effects of Aβ on CBF and neurovascular coupling are becoming more evident. This review will describe AD vascular disturbances as they relate to Aβ, including chronic cerebral hypoperfusion, hypertension, altered neurovascular coupling, and deterioration of the blood-brain barrier. In addition, we will describe recent findings about the relationship between these vascular defects and Aβ accumulation with emphasis on in vivo studies utilizing rodent AD models.

The Accumulation of Tau-Immunoreactive Hippocampal Granules and Corpora Amylacea Implicates Reactive Glia in Tau Pathogenesis during Aging.

SummaryThe microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.

Mechanisms of Electroacupuncture on Alzheimer's Disease: A Review of Animal Studies.

Alzheimer's disease (AD) is the main type of dementia affecting elderly people. The medicines used for treating AD have limits in their ability to alleviate cognitive and functional decline. Electroacupuncture (EA), an economical alternative and complementary therapeutic measure used in Chinese medicine, has strong clinical applicability, and its treatment effects are more reliable as its stimulation factors can be standardized. EA has been effectively used for ameliorating spatial learning and memory impairment in AD patients and rodent AD models. Here, we summarized the mechanisms of EA on rodent AD models, aiming to provide a theoretical basis for identifying new targets and research directions, and exploring appropriate EA stimulation parameters, then provide a detailed methodology to optimize the effects of EA, ultimately reducing the heavy burden of treating AD patients on families and countries. Our review showed that 8 acupoints were used when treating AD animals; Baihui (GV 20) was the most frequently used. Four mechanisms of EA were studied: (1) protection of cerebral neurons from oxidative stress, apoptosis, neuroinflammation, synaptic plasticity and hormone levels; (2) regulation of metabolism, including glucose metabolism and plasma metabolism; (3) regulation of brain-derived neurotrophic factor; and (4) regulation of β-amyloid peptide protein deposition.

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer's Disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Symptoms of AD include memory loss, disorientation, mood and behavior changes, confusion, unfounded suspicions, and eventually, difficulty speaking, swallowing, and walking. These symptoms are caused by neuronal degeneration and cell loss that begins in the hippocampus, and later in disease progression spreading to the rest of the brain. While there are some medications that alleviate initial symptoms, there are currently no treatments that stop disease progression. Hippocampal deficits in amyloid-β-related rodent models of AD have revealed synaptic, behavioral and circuit-level defects. These changes in synaptic function, plasticity, neuronal excitability, brain connectivity, and excitation/inhibition imbalance all have profound effects on circuit function, which in turn could exacerbate disease progression. Despite, the wealth of studies on AD pathology we don’t yet have a complete understanding of hippocampal deficits in AD. With the increasing development of in vivo recording techniques in awake and freely moving animals, future studies will extend our current knowledge of the mechanisms underpinning how hippocampal function is altered in AD, and aid in progression of treatment strategies that prevent and/or delay AD symptoms.