Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain involving neuropathological hallmarks such as deposition of plaques of amyloid-beta (Aβ) (outside nerve terminals), the existence of neurofibrillary tangles (NFTs- inside the neurons) produced by aberrantly hyper phosphorylated tau, progressive synaptic loss and neuron degeneration which further leads to decline in memory and cognitive functions as shown in Fig. (1) [1, 2]. For quite a long time, AD research has concentrated on the two obsessive neuropathological signs of the disease, i.e., amyloid plaques and NFTs. In spite of the fact that amyloid-beta conglomeration and NFTs development are notable major causative components engaged with AD pathogenesis, the researchers failed to cure or prevent the progression of disease effectively by focusing on these pathogenic variables. Tackling AD is a complex job, as we have erudite lately by continuous phase III clinical trial programs failures. The majority of these projects depended on the focusing of Aβ, prompted by amazing research discoveries that Aβ can be cleared from the human mind. Albeit some Aβ-bringing down compounds have applied quantifiable impacts on psychological results, these impacts have commonly been too little to even consider being genuinely critical and clinically significant [3]. Generally, AD is of two types; one is familial Alzheimer’s disease (FAD) and other sporadic Alzheimer’s disease (SAD), which is also known as early-onset of AD (EOAD) and late-onset AD (LOAD), respectively. Heredity of specific genes is a danger factor for AD, with both familial and sporadic cases happening. Genetic variations in amyloid precursor protein (APP), beta-secretase, and in presinilin-1 (PS1) and presenilin-2 (PS2) genes are thought to be liable for disease production in the FAD. Whereas, in SAD, which is the more normal category, there is a connection with the apolipoprotein 4 (APOE4) allele. The danger is more noteworthy in homozygotic circumstances and metabolic cycle disturbance [4-7]. In addition, ecological elements, vascular components, and psychical factors likewise add to the evolution of SAD. As of now, no medications are accessible to end the occurrence of neurodegeneration in AD; the idea of AD treatment is suggestive. For example, acetylcholinesterase enzyme inhibitors, Donepezil (brand name Aricept), Galantamine (Reminyl), Rivastigmine, and Tacrine (Cognex), that advance cholinergic neuronal signaling are utilized in gentle to direct instances of AD [8]. An alternate sort of medication, memantine (Namenda), antagonize N-methyl-D-aspartate (NMDA) receptor, may likewise be utilized, alone or in the mix with a cholinesterase enzyme inhibitor in moderate to serious cases to forestall excitotoxicity, and antipsychotics and antidepressants are utilized in the treatment of neuropsychiatric side effects [9]. At present, there is no established way to cure AD although research into prevention strategies is ongoing. Due to its complexity, it is far-fetched that any one medication or other intercessions can effectively prompt its legitimate treatment. Recent approaches center around assisting individuals with keeping up mental capacity, overseeing social side effects, and moderating or deferring the manifestations of illness [10, 11]. Scientists desire to create treatments focusing on explicit hereditary, sub-atomic, and cell systems with the goal that the genuine hidden reason for the sickness can be halted or forestalled.
Fig. (1))
Molecular mechanism in inhibit A-beta production, clearance, and prevent aggregation. APP: Amyloid precursor protein; AICD: APP intracellular domain; Aβ: Amyloid-beta; BACE: beta-site APP cleaving enzyme 1.
The biggest problem in AD drug development is doubtful mechanisms inherent AD pathogenesis and pathophysiology. Several reported research and existing literature aid the concept that AD is a complex illness. While there is ample manifestation that amyloid plaque is responsible for the pathogenesis of AD, other possible mechanisms have been involved in AD-like tangle formation (tau-tangle) and outspread, neuroinflammation, and altered protein degradation pathways. Therefore, the present-day epitome of AD drug design and development has been modified from a one-on-one target area to a multi-target approach. Here, in this chapter, we will also sum up current techniques and a new way of drug development in the area of AD research, including animal-based (pre-clinical) and human-based (clinical trials), studies that mark on the various facet of the disease [12]. As we know, animal models intended to be used for examining human sicknesses came out in the 1800s and presented a leading hike during the last few decades. Rodents models are primary tools in the field of biomedical research, including AD [13]. The animal models mimic different types of AD-like pathological conditions, which is an essential component in discovering potential therapeutic targets and studying the mechanism of action behind that therapeutic agent. They are also helpful in the development and assessment of mechanical hypotheses about neurological and neurodegenerative disorders, including AD, and in identifying and screening novel therapeutic agents. Several rodent models are present to interpret the basic underlying pathological mechanism of AD and screen novel therapeutically active agents for the treatment of AD. Although the rodent models do not reproduce true clinical conditions of the AD, however, neuropathological similarity to human AD patients make them a valuable mean of studying AD pathology [6]. The real value of an animal model and its applicability are ascertained by various levels of validity [14, 15], as depicted in Table 1.
Table 1Animal models: levels of validity.S.No.ValidityDescription1.Etiological validityEquivalent etiologies of occurrence in the model and the human issue2.Face validityLikeness between the model, and the circumstance or interaction being displayed, e.g., likeness of manifestations.3.Construct validityComparable cell, and molecular activities in the rodent model and human patients, which help in studying fundamental pathophysiological mechanisms in the model.4.Predictive validitySymbolize pharmacological isomorphism implies a model recognize compounds with possible restorative impacts in the human condition
The more degrees of legitimacy a model fulfills, the more prominent its worth, utility, and pertinence to the human condition. However, generally, animal models do not meet all of these criteria. Generally, the most common manifestation of AD is cognitive decline. The final output signal for any intercessions ought to be assessed by the trial of learning and memory. Although countless rodent models and behavior assessment strategies have been extensively utilized in studies of underlying mechanisms and screening of novel remedial moieties, a big variableness still exists within the methodological analysis, particularly in how rodent models are being used and why the specific one. For selecting a suitable and effective model for AD research studies, it is crucial to realize the basic fundamental properties and relevance of the animal models and behavioral change screening methods [16]. This chapter also provides a brief summary of in-vivo/ex-vivo, in-vitro, QSAR or in-silico models that are commonly used in AD research.
Current AD Therapeutic Strategies and Targets
In this section, we are focusing on current AD restorative techniques which involve system based methodologies including Aβ drainage, tau protein stores, ApoE capacity, neuroprotection, and neuroinflammation, just as non-mechanism based methodologies including indicative psychological incitement, AD anticipation, way of life adjustments, and hazard factor the executives including non-pharmacological intercessions [12] as shown in Fig. (2). Here, we also described AD drugs and targeted therapies studied in clinical trials (Table 2). Moreover, we also provide a brief description of behavioral models (Table 3), chemically induced animal models and their reported studies (Tables 4 & 5), transgenic animal models (Table 6), miscellaneous animal models (Table 7) of AD. Later, we described in-vitro models (Table 8) and experimental species used for AD and their significance and limitations (Table 9) and also depicted translational concerns with animal models in AD (Fig. 3).
Fig. (2))
Current AD therapeutic strategies and targets. Aβ: amyloid-beta, AD: Alzheimer’s disease, ApoE: apolipoprotein-E.
Table 2AD drugs and targeted therapies studied in clinical trials [12].DrugsPhaseSubjectSummaryReferencesAmyloid based approach1. Lessening Aβ productionMK-8931 (BACE inhibition)ThreeEarly ADLack of efficacyNCT01953601LY450139
(γ-secretase inhibition)ThreeLenient to medium ADDiminished efficacyNCT00762411, NCT00594568, NCT01035138AvagacestatTwoEarly ADNo successNCT00890890NIC5-15TwoPredictable ADCompletedNCT01928420R-flurbiprofenThreePredictable ADLack of efficacyNCT00105547; NCT00322036EVP-0962TwoHealthy, mild cognitive impairment or early ADTerminatedNCT016616732. Accelerating Aβ ClearanceAN-1792TwoLenient to medium ADTerrible meningo-encephalitisNCT00021723Affitope AD02TwoEarly ADNo efficacyNCT02008513, NCT01117818CAD106Two/ threeLenient ADOngoingNCT02565511BapineuzumabThreeLenient to medium ADNo efficacyNCT00667810, NCT00575055, NCT00574132SolanezumabThreeLenient to medium AD and predictable ADNo efficacyNCT00905372,NCT00904683, NCT01900665BAN2401TwoMild cognitive impairment and Lenient ADSupportive outcomesNCT01767311CrenezumabThreePredictable AD or early ADOngoingNCT03114657, NCT02670083GantenezumabThreePredictable AD or early ADOngoingNCT03443973, NCT03444870AducanumabOne/ threeEarly or Lenient AD/
MCI due to AD or Lenient ADSupportive results/ongoingNCT01677572/
NCT02484547, NCT024778003. Some other anti-amyloidogenic agentsALZT-OP1ThreePrompt ADOngoingNCT02547818GV-971ThreeLenient to medium ADCompletedNCT02293915PosiphenOneMCI or predictable ADOngoingNCT02925650ELND005Two/ threeLenient to serious ADOngoing--ALZ801ThreeLenient ADIn progress--Targeted at Tau1. Tau-protein stabilizers and conglomeration inhibitorsTPI287OnePredictable ADOngoingNCT01966666Rember™TwoLenient or medium ADNo efficacyNCT00684944, NCT00515333TRx0237ThreeLenient to medium ADNo efficacyNCT01689233, NCT01689246, NCT02245568TauRxTwo /threeLenient to medium ADOngoingNCT035393802. Treatments focused at tau post-translational changesLithium and ValproateTwoADNo successNCT00088387NP-12Two bLenient to medium ADNo successNCT013503623. Against tau immunotherapyAADvac1TwoLenient to medium ADOngoingNCT02579252ACI-35TwoLenient to medium ADCompletedISRCTN13033912ABBV-8E12TwoMild cognitive impairment or predictable ADOngoingNCT03391765, NCT02880956RO7105705OneHealthyOngoingNCT02820896Strategy focused on ApoEBexaroteneTwoPredictable ADNo successNCT01782742Strategy focused on neuroprotection1. Treatment based on neurotrophins and their receptorNGFOnePredictable/ early ADPositive outcomesNCT00017940AAV2-NGFTwoLenient to medium ADNo efficacyNCT00876863LM11A-31One/ twoLenient to medium ADOngoingNCT030690142. Strategy directed at neuroinflammation and oxidative stressDimebonThreeADNo successNCT00912288ValacyclovirTwoPredictable ADOngoingNCT03282916Indicative Cognitive IntensifierIdalopirdine (5-HT6 antagonist)Two/ threePredictable AD/ lenient to medium ADBeneficial outcomes/ no efficacyNCT01019421/NCT01955161, NCT02006641, NCT02006654GSK239512 (H3R antagonist)TwoPredictable ADNo successNCT01009255ABT288 (H3R antagonist)TwoLenient to medium ADNo successNCT01018875Rasagiline (MAOB inhibitor)TwoPredictable ADOngoingNCT02359552Ladostigil (combined)TwoMild cognitive impairment or lenient to medium ADNo successNCT01429623, NCT01354691AZD0530One bLenient to medium ADWell-being and bearableNCT01864655Cilostazol (PDE 3 inhibitor)Two/ FourMild cognitive impairment/lenient to medium ADPositive outcomes/ in progressNCT02491268, NCT01409564HT-0712 (PDE4 inhibitor)TwoAge-related impaired memoryCompletedNCT02013310Roflumilast (PDE4 inhibitor)One/ twoScopolamine-induced Cognitive impairment/ healthy/ age-associated memory impairmentNo efficacy/ positive outcomes/ completedNCT02051335/NCT01433666/ ISRCTN96013814BPN14770 (PDE4 inhibitor)OneHealthyPositive outcomesNCT02648672, NCT02840279BI 409306 (PDE4 inhibitor)One/ twoHealthy/ Mild cognitive impairment and lenient ADSafety and tolerance/ in progressNCT01343706/ NCT02337907PF044467943
(PDE4 inhibitor)One/ twoLenient to medium AD/ lenient to medium ADSafety and tolerance/ no efficacyNCT00988598Treatments and Interventions for Prevention of ADPROSPER (statin)TwoHigh risk (with AD parents)No successNCT00939822ACCORD-MINDThreeDiabetes mellitus 2No successNCT00182910SNIFFTwo; two/ threeMild cognitive impairment or AD or predictable ADOngoingNCT00438568; NCT01767909MetforminFourAge >60 yearsCompletedNCT02432287PioglitazoneTwoLenient to medium ADWell-being and toleranceNCT00982202MIND (diet)--Basal metabolic index ≥25 non-dementedOngoingNCT02817074FABS (fitness)--Non-dementedBeneficial outcomesACTRN12605000136606ACTIVE (cognitive training)Two/ threeMild cognitive impairmentBeneficial outcomesNCT00298558Vit. E + MemantineThreeLenient to medium ADBeneficial outcomesNCT00235716Ginkgo bilobaThreeNon-demented and Mild cognitive impairmentNo successNCT00010803EGb 761®FourSubjects with memory complaintsNo successNCT00276510MIDAS--Age-associated memory impairmentBeneficial outcomesNCT00278135FINGER--High riskBeneficial outcomesNCT01041989MIND-ADMINI--Early ADOngoingNCT03249688
Table 3Commonly used behavioral model in AD [17].ModelDescriptionCognitive DomainSignificanceLimitationReferencesMorris water maze (MWM)Generally utilized conduct task where mice are set in a roundabout pool and should track down a secret escape platform.Work and reference memory-It is most similar to human tasks
-Very much adjusted to the investigation of specific visuospatial factors set up learning and working memory
-Speedy-It is undoubtedly more stressful compared to the Barnes Maze and RAM
-Less appropriate for rehashed measures or for evaluation of long term memory deficiencies
-Failure to find the platform is potentially life-threatening[18-20]
The MWM is aversively propelled by the longing to escape onto a protected stage, while the RAM is inspired by a food reward. This distinction in reinforcement may influence the speed of learning, the technique received, and the need for a precise route.acquisition
-Route essentially through allocentric visuospatial signs
-Highly sensitive for assessment of
damage to hippocampus
-No need for former preparations such as feed and water discontinuation in animals
-Because of the water pool in this apparatus, it disposes off the odds that rodents utilize fragrant prompts to arrange themselvesRadial Arm Maze (RAM)The apparatus normally comprises 6–8 arms emanating from a round focal space. Different arms are teased with a food rewardWork and reference memory-RAM distinguishes consistent state reference and working memory shortages and is suitable for repeated measures
-Inability to discover a food reward brings about no incredible punishment, aside from when the rodents are exceptionally ravenous-Acquisition required a long time
-Extra effort or strategies may help route instead of special cues[18, 19, 21]Radial Arm Water Maze (RAWM)A submerged variant of the RAM where the food reward is supplanted by an escape stageWork and reference memoryRefer MWMRefer MWM[18, 19, 22]Barnes mazeComprises of a roundabout stage with openings around the periphery and a getaway boxWork and reference memory-It is increasing in popularity while the MWM has been decreasing due to cost, complexity, and unnecessary stress on mice and rodents
-Does not utilize a strong aversive stimulus (as in MWM) or deprivation of food and water (as in RAM)
-Especially reasonable for mice since these rodent display a lower execution in MWM-Learning is moderate or even missing sometimes
-It can likewise animate non-spatial techniques like a sequential methodology that would then be able to influence the execution
-Chances that rodents utilize sweet-smelling signals to situate themselves[18, 23, 24]T-Maze/Y- MazeA three-arm apparatus powers the rodent to pick between two armsWork and reference memory-Least difficult apparatus to evaluate spatial working memory
-Doesn't need an automatic video recording system
-Provides highly
reproducible results-Major disadvantage that it has only one decision point with two other options, which builds the chances of progress (naturally the likelihood of picking the right arm is half)
-Requires constant handling of animals which results in inducing stress in animals
-Chances that rodents utilize sweet-smelling signals to situate themselves[18, 25, 26]Novel Object Recognition (NOR)A two-preliminary memory task which utilizes the rodent's inborn exploratory conduct to evaluate memoryRecognition memory-Requires no outside inspiration, award, or discipline, a tiny bit of preparing or habituation is required
- Does not require deprivation of food and water (as in RAM)-Try not to consider proportions of learning[27, 28]Contextual and cued fear conditioning (Pavlovian learning)The rodents figure out how to foresee an unpleasant stimulus dependent on a related setting/ signalReference (associative learning) memory-Used in the phenotyping of transgenic mice
-Passive learning
-Help in study the role of the hippocampus in managing the learning of the setting where an unfortunate occasion occurred
- No need for water and feed deprivation to an animal to prove fear conditioning-Stress inducing in animals due to aversive stimulus
-Strains having sensory deficits unsuitable for studies of fear conditioning
-Sensitivity to a stressful environment or handling[29, 30]Passive avoidanceAn evasion task where the rodent should abstain from entering a chamber where an unpleasant signal was recently directedReference (associative learning) memoryRefer Pavlovian learningRefer Pavlovian learning[31]Active avoidanceAn awful-motivated acquainted evasion test where a rodent should effectively stay away from an unpleasant signalReference and work (associative learning) memory-No need for food or water deprivation to animal
-Active learning-Sensitivity to a stressful environment or handling
-apparatus should be placed in a soundproof or quiet room to minimize external noise during the tests[32]Delayed Matching (non-matching) to Position / Sample (DMTP/ DMTS)The rodent gets a sample signal, and afterward, a brief pause, is needed to pick the right related reactionWork memory----[33, 34]Multiple-Choice Serial Reaction Time Task (CSRTT)The animal should take care of a few spatial areas (normally 3–5), notice a comparing boost, and afterward accurately reactConsideration, impulsivity, enforcement action----[35]Attentional set-shifting tasksThe animal must shift back and forth between changing rules to successfully obtain a rewardExecutive function and cognitive flexibility----[36]Reversal learningAdjustment to changes in reward contingencyExecutive function and working memory----[37, 38]What-Where-Which Task (WWWhich)The animal should relate an item (What) with its area (Where) in a particular visuospatial setting (Which) to frame an incorporated memoryRecognition and episodic-like memory----[39, 40]
Table 4Chemically induced animal models of AD.Chemically Induced ModelMechanism of ActionDescriptionFindingsReferencesHeavy metal induced cognitive deficit (Aluminium-Al commonly used, other copper-Cu, zinc-Zn, lead -Pb)-Dysfunctional tubulin
-Neurotransmitter imbalance (Cholinergic dysfunction)
-ROS
-Oxidative stress
-Increase APP gene expressionThey are commonly known to damage the nervous system. The effect of Al well reported on biological system as compared to other heavy metals. Subjects suffering from AD presenting high levels of Al in the brain. OrallyIn the Al-induced group, marked histopathological alteration and spread gliosis joined by pericellular edema in the cerebral locale.
-Neuronophagia and loss of neurons[41-43]Apoptosis of neuronal cells
-Phosphorylation of tau
-Aβ 42 accumulation
-upregulation in response and expression of AChE and MDA
-Significant reduction in action and expression of GST, GPx, and GRadministered Al (300 mg/kg body weight) was accounted for to actuate oxidative stress, cholinergic shortfall, and aggregation of Aβ and NFTs in the mind of rodents (rats).In the Al-induced group, marked histopathological alteration and spread gliosis joined by pericellular edema in the cerebral locale.
-Neuronophagia and loss of neurons[41-43]Streptozotocin (STZ) induced-Neurotransmitter disturbance
-Oxidative stress
-Overactivation of GSK-3β
-Decrease alpha-secretase activity
-Increase MDA level
-Increase lipid peroxidation
-NeuroinflammationSTZ, derivative of glucosamine nitrosourea and recovered from the strain of Streptomyces achromogenes. ICV-STZ administration in rodents notable to apply a serious and enduring impact on mind artifact, its natural chemistry, metabolism, and functional characteristics such as declined glucose and energy consumption, oxidative stress, and cognition. STZ can cause neuronal damage and tau hyperphosphorylation, which further results in the generation of ROS and RNS.
ICV-STZ (3 mg/kg, ICV) as a model of intellectual hindrance in rodents impersonated the sporadic type of ADDestroy the glycolytic enzyme activity within the brain, followed by low levels of ATP. Furthermore, damaged energy framework and altered acetyl CoA formation can stop conduction in cholinergic neurons.
Increased activities of AChE within brains of rodents and reduced levels of ACh. STZ also modifies GSK 3α/β, which leads to the formation of Aβ peptide-like aggregates.Advantage: The long-lasting effects observed with ICV-STZ mimicked the condition of AD patients[44, 45]Colchicine induced-Decrease activities of AChE & ChAT
-Oxidative damage
-Increase expression of iNOS
-Generation of ROS
-Increase expression of COX 1-2
-Increases Glutamate/GABAIt actuates hippocampal injuries bringing about psychological debilitations and ChAT decrease, proposing that it tends to be used as a possibility for demonstrating AD. It can cause neurotoxicity and memory decay by hindering cholinergic pathways, in this manner prompting a decrease in the quantity of cholinergic neurons and hence diminishing cholinergic recharging initially inside the hippocampal space. Memory hindrance might be because of the decline in serotonin, dopamine, and norepinephrine inside the caudate core, hippocampus, and whole cerebral cortex. Colchicine (7.5 g in 10 L, ICV) was found to reiterate psychological memory decrease in rodents.
Critical memory deficiency saw following fourteen days of enlistment of intellectual disability.Increased level of COX-1 and COX-2 articulation and ROS formation. Increased level of glutamate / GABA ratio in the brain cortex and eventually triggers MDA receptors activation, which further leads to acute increment in Ca2+ influx, so that resulting in the activation of enzymes that based on Ca2+ signalling (e.g., cyclooxygenases,
phospholipases A2, proteases, protein kinases, and xanthine oxidase).Advantage: it causes a few indications of sporadic type Alzheimer's disease, practically equivalent to those related with human subjects, for example, time-variation changes in beginning, social, and physiological patterns[46-48]Ethanol-induced-Oxidative stress
-Enhances the extracellular level of adenosine
-Decrease BDNF expression
-Glutamate & GABA imbalance
-Apoptotic neurodegeneration in developing brainAlcohol intake, chronically is associated with numerous difficulty such as attention deficits, language disability, hyperactivity, motor dysfunction and learning deficits with reduced social activities. Its consumption results in ROS generation leads to decreases levels of antioxidantsDamage cholinergic and hippocampal neurons Disruption of learning and memory.
Huge consumption leads to excessive NO production, which results in memory and learning deficits. It also elevates the adenosine level, which may result in memory damage.Limitation: Lack of exact molecular mechanisms still needs further investigations.[49, 50]Okadaic acid-induced-Stimulate hyperphosphorylation of tau protein and neuronal cell death
-ROS generation leading to mitochondrial dysfunction
-Increased expression of GFAP and lowers glutathioneOkadaic acid is a significant polyether poison begun from marine microalgae.Reduced transmission across a synapse. Synaptic plasticity inhibition. Increased Ca2+ in cultured hippocampal neuron results in neuronal loss.
It triggers ROS generation in the hippocampus, suppresses mitochondrial action and power, at long last outcomes in mitochondrial irregularities in rodents minds.
Exacerbated proinflammatory cytokines (TNF-α and IL-1, and with iNOS)..[51-54]Okadaic corrosive is antagonize serine/threonine phosphatases 1 and 2A, which is connected to short- and long-term memory disturbance in rodents, and ultimately starts tau hyperphosphorylation and neuron destruction in in-vivo as well as in in-vitro.
Bilateral infusion of Okadaic acid in the hippocampus results in increased GFAP articulation, diminished GSH, upgraded protein carbonylation, and p38MAPK.
Advantage: Presently, chemicals obstructing tau phosphorylation are not accessible. Subsequently, this model could be a helpful substitution instrument for unwinding restorative methodologies for AD pathology.Sodium azide (NaN3) induced-Increases myeloperoxidase
-Decreases cholinergic input into the hippocampus
-Increases the AChE and nitrite activity
-Generation of free radicals
-Decreases mitochondrial respiratory chainSodium azide (NaN3), a white crystalline solid, mitochondrial toxin. It induces mitochondrial dysfunction and inhibit cytochrome oxidase (mitochondrial complex-IV) and diminishes ATP levels, which further prompts metabolic debilitation and ROS production, eventually creating AD-like condition. Induction of AD is usually confirmed in this model by neuronal loss in the CA3 hippocampus region.Impaired learning and memory, increases AChE levels, causes oxidative damage that resulted in neurons death.
Tissue damage were seen in the cortical and hippocampal spaces of treated rodents.[55-57]Lipopolysaccharide (LPS) induced-Oxidative and inflammatory stress
-Increase Aβ42 deposition in hippocampus
-Increases β-secretase and γ-secretase activity in hippocampus and cortex
-Decrease the level of glutathione and MDA contentLPS has been known to be utilized in different analyses, both in vitro and in vivo models of amyloidosis and neuroinflammation. It is acquired from the outer film of gram negative microbes. It go about as a solid endotoxin, showing protection from degradation by mammalian enzymes, along these lines, results aggravation by delivering proinflammatory cytokines. At that point, these proinflammatory cytokines activate neuroimmune just as neuroendocrine system.After 3 days of LPS treatment, observed upregulated amount of TNF-α, IL-6, and IL-1β, inside the hippocampus as compared to control[58-61]Scopolamine induced-Stimulation of GSK-3β
-Dendrite aborisation associated with alteration in CREB and AMPA receptor
-Blocks binding site of ACh
-Increases AChE activity
-Increases MDA levels and lipid peroxidation
-NMDA receptor mechanisms
-Blocks long term potentiationIt non-specifically blocks the bond site of ACh muscarinic receptors in the cerebral cortex and results in the inconsistent release of ACh, which destroys hippocampal neurons and instigates learning and memory impedance in mice in a dose-related wayScopolamine administration prompts shortages in visual reference memory, verbal review, visuospatial praxis, visuospatial review psychomotor speed, and visuoperceptual measures. Hippocampal administration of it occludes LTP and impedes spatial encoding[62-64]Aβ 1-42 and 1-40 inducedNeurotransmitter disturbance
-Oxidative stress
-Overactivation of GSK-3β
-Decrease alpha-secretase activity
-Increase MDA level
-Increase lipid peroxidation and nitrite
-Decreased GSH, SOD, and catalase
-Neuroinflammation
-Increase Aβ42 deposition in the hippocampus
-Increases β-secretase and γ-secretase activity in hippocampus and cortex
-Blocks long term potentiationAβ plaque is the major neurotic trademark in AD and direct infusion of Aβ into the cerebrum causes neuronal dysfunction, neurodegeneration and learning and memory debilitation. One investigation from our lab showed that intrahippocampal Aβ42 induced rodent mind causes huge memory and learning misfortune just as results in altered mitochondrial function and oxidative stress.Memory and learning loss, mitochondrial dysfunction and oxidative stress etc.[65]Ibotenic acid induced-Act as an excitotoxin
-Increased AChE activity
-Increased MDA levels
-Neuronal toxicityIbotenic acid- a strong neurotoxin that exacerbate signs and pathophysiology similar to AD.
Ibotenic acid (5 µg/µl PBS, IH) causes memory dysfunction and neuronal toxicity.Increased AChE activity and MDA levels.
Reduced activity of cholinergic neurons in rats[66, 67]Kainic acid induced-Act as an excitotoxin or neurotoxin
-Increased LPO and nitrite
-Decreased SODKainic acid (0.4 µg/2µl, IH) administration followed to redox damage and memory loss in ratsIncreased lipid peroxidation and nitrite level.
Diminished SOD.[65]
ACh: acetylcholine; AChE: acetylcholinesterase; AMPA: amino-3-hydroxy-5-methyl4-isoxazole propionic acid receptor; APP: amyloid precursor protein; BDNF: brain derived neurotrophic factors; ChAT: cholineacetyltransferase; COX 1 & 2: cyclooxygenase 1 & 2; GABA: gamma amino butyric acid; GFAP: glial fibrillary acid protein; GPx: glutathione peroxides; GR: glutathione reductase; GSK-3β: glycogen synthase kinase-3 beta; GST: glutathione-s-transferase; ICV: intracerebroventricular; iNOS: inducible nitric oxide; IH: intrahippocampal; LTP: long-term potentiation; MDA: melondialdehyde; NFTs: neurofibrillary tangles; NMDA: N-methyl-D-aspartate; NO: nitric oxide; p38MAPK: mitogen-activated protein kinase 38; ROS: reactive oxygen species; RNS: reactive nitrogen species; STZ: streptozotocin; SOD: superoxide dismutase.
Table 5Various reported studies using chemical-induced AD models [68].S. No.Chemical UsedSpecies (Age/ Weight/ Dose/ Study protocol)Behavior AssessmentBiochemical AnalysisReferences1.Aluminium (Al)Rat (150-170g, 50 mg/kg 3 times a week orally, 90 days)Cognitive disturbance and slow locomotor activity-Decrease AChE, catalase and GSH levels[69]2.Aluminium and copper (Al & Cu)Female SD rat (170-200g, 5mg/kg, 20mg/kg and 50mg/kg, 40 days)Significant deficit in the learning activity-Decreased GSH, SOD, GST and GPx
-Increased TNF-α, IL-1β
-Increased AChE level
-Increased APP gene expression and oxidative stress[70]3.Aluminium chloride (AlCl3)Rat (180-200g, 300mg/kg, orally, 60 days)Spatial learning and memory impairment-Increase AChE activity
-Increased TNF-α, IL-1, IL-6
-Increased BDNF level
-Decreased CAT, GSH and MDA[71]4.Aluminium chloride (AlCl3)Rat (250-300g, 17mg/kg, orally, 12-15 week old, 21 days)Impaired cognitive function and decrease in deteriorated memory as a decrease in time to reach food-Increased IL-6
-Decreased ACh
-Decreased BDNF level and AChE activity
-Decreased DA
-Amyloid plaque production[72]5.Aluminium chloride (AlCl3) + D-galactoseRat (280-300g, 10 weeks, 300mg/kg and 60mg/kg, orally and intraperitonealDecreased time spent in target quadrant-Increased AChE activity[43]6.ICV-STZRat (280-300g, 0.5mg/kg (3-5 weeks), 1mg/kg (9-11 weeks), 3mg/kg onceMarked debilitation in working memory-Decreased ChAT expression
-Decreased insulin receptor (IR) expression[73]7.ICV-STZRat (350-400g, 2mg/kg, 3-4 months)Cognitive deficit-Decreased synaptop- hysin[74]8.ICV-STZMice (20-25g, single dose, 2 weeks)Decreased learning and memory as diminished time spent in the target quadrant in MWM-Reduced alpha- secretase activity
-Decreased level of Aβ42, β-secretase, and COX-2[75]9.ICV-STZRat (220-250g, 5µl, 3months)Decreased spatial learning and memory in MWM and passive avoidance task-Increased oxidative stress
Decreased GSH and MDA levels[76]10.ICV-STZRat (300-350g, 3-4 months, 30 days)Memory impairment observed as reduced time spent on the new arm in Y-maze (spatial memory), short term recognitionNeuro- inflammation[77]11.ScopolamineRat (150-250g, 20g/kg, i.p.)Memory deficit and increased conditional avoidance-Increased MDA, LPO
-Increased AChE activity -Decreased GSH level[62]12.ScopolamineRat (200-220g, 1mg/kg, i.p.)Marked memory impairment as delayed latency to target quadrant in MWMOccluded cholinergic signals[64]13.ScopolamineRat (150-200g, 2.5mg/kg, orally)Memory impairment-Increased AChE activity -Decreased GSH and GABA levels[78]14.ScopolamineMice (20-25g, 1mg/kg; i.p, 8 weeks old)Impaired learning and memory-No change on AChE activity[63]15.ScopolamineMice (17-24g, 10mg/kg; i.p, 7-12 weeks)Impaired learning and memory-Increased cholinergic neuron expression[79]16.ICV-ColchicineRat/Mice (200-260g rat; 25-30g mice, 7.5µg in 2.5µl aCSF)Memory loss-Increased TNF-α, ROS, COX2 and nitrite[80]17.ICV-ColchicineRat (180-200g, 15µl/5µl aCSF, 21 days)Marked memory loss-Decreased GSH, SOD, GST
-Increased MDA levels
-Increased AChE activity[47]18.ICV-ColchicineRat (180-200g, 15µl/15µl aCSF, 21 days)Cognitive impairment, learning deterioration-Increased MDA levels
-Decreased GSH and AChE activity
-No change on catalase[81]19.ICV-ColchicineRat (180-200g, 15µl/rat, 3 weeks)Impaired acquisition in spatial navigation task and memory impairment-Decreased GSH
-Increased ROS and Aβ peptide deposits in the hippocampus[82]20.ICV-ColchicineRat/Mice (200-250g rats, 20-30g mice, 7.5µl in 2.5µl, 6-8 weeks old)Memory impairment-Increased TNF-α, ROS, and nitrite[83]21.IH-Okadaic acidRat (200-320g, 90 days, 100mg, 12 days)Decreased latency to platform-Decreased GSH and oxidative stress[84]22.ICV-Okadaic acidRat (200-320g, 90 days, 100mg, 12 daysDecreased latency to the platform and spatial cognitive deficit-Decreased GSH, oxidative stress, tau phospho- rylation[85]23.ICV-Okadaic acidSD Rat (220-250g, 200mg, 13 days)Poor memory performance-Increased MDA, GSH, and nitrite
-Decreased GSH and LPO[86]24.ICV-Okadaic acidMice (20-22g, 200ng, 2 times in 3 days interval)---Decreased GPx
-Increased MDA[87]25.EthanolMice (18-22g, 12ml/g once daily in 1st week and then twice daily, orally)Cognitive impairment and during spontaneous movement short distanced covered by animals-Increased TNF-α and IL-1β
-Decreased glutamate and GABA
-Imbalanced Neurotrans- mitter[88]26.EthanolSD Rat (250-300g, 5g/kg, 2-4 days, orally)Learning and memory deficit-Increased TNF-α in the hippocampus
-No change on BDNF levels[89]27.EthanolRat (180-200g, 396-426 g, long exposure, orally)Impaired memory--[90]28.EthanolSD Rat (200-300g, 4.5mg/kg, 21 days, orally)---Increased AChE activity[91]29.EthanolRat (150-220g, 4.5g/kg, 21 days, orally)Decreased discrimination index in novels object discrimination-Decreased AChE activity and oxidative stress[92]30.ICV- Lippo- polysaccharides (ICV-LPS)SD Rat (200-220g, 2µl/1min, 21 days)Loss of spatial memory and reduction in sniffing times-Increased IL-1β in hippocampus
-Increased COX-2, NFkB, iNOS[93]31.IH- Lippo- polysaccharides (IH-LPS)Mice (18-22g, 40µg/mouse single dose, 7 days)Learning and memory impairment, increased latency to find platform using MWM, and spontaneous alteration in Y-maze-Decreased TNF-α, NO and IL-6
-Microglial activation in CA1 and DG region of the hippocampus[60]32.Lippo- polysaccharides (LPS)ICR Mice (250µl/kg, i.p, 7times daily)Memory deficit-Decreased TNF-α, IL-1β and IL-6
-Decreased GSH/GSSG
-Decreased COX-2 and iNOS
-Decreased MDA level[59]33.Lippo- polysaccharides (LPS)SD Rat (250g, 10mg/kg, i.p, single dose, 7-9 days)---Increased TNF-α, IL-1β and IL-6[58]34.Lippo- polysaccharides (LPS)ICR Rat (0.25mg/kg, i.p, 2 months old, 21 days)Spatial memory deficit and decreased latency-Increased Aβ42 in the cortical and hippocampal region of the brain
-Increased activity of enzyme- β-secretase
-Increased γ-secretase activity in frontal cortex and hippocampus
-Increased COX-2, iNOS and GFAP[94]
AChE: acetyl cholinesterase, ACh: acetylcholine, ChAT: choline acetyltransferase, MDA: Melondialdehyde, SOD: Superoxide dismutase, iNOS: inducible nitric oxide, GSH: glutathione, GPx: glutathione peroxidase, CAT: catalase, DA: dopamine, BDNF: brain derived neurotrophic factors, NO: nitric oxide, ROS: reactive oxygen species, ICV: intracerebroventricular, IH: intrahippocampal, STZ: Streptozotocin, SD: Sprague-Dawley, IP: intraperitoneal, LPS: Lippolyssacharide, TNF-α: Tumor necrosis factor, GST: Glutathione S-transferase, GFAP: Glial fibrillary acid protein.
Table 6Single transgenic/knock-in/knock-out mouse and rat model used for AD (Source: www.alzforum.org).ModelSpeciesMutationGeneABCA7 gene basedAbca7*A1527G/APOE4/Trem2*R47H
(Modification: Abca7: Knock-In; APOE: Knock-In; Trem2: Knock-In)Mouse (C57BL/6J)Trem2-R47HAbca7, APOE, Trem2Abca7KO/APOE4/Trem2*R47H (Modification: Abca7: Knock-Out; APOE: Knock-In; Trem2: Knock-In)Mouse (C57BL/6J)Trem2-R47HAbca7, APOE, Trem2APLP2 gene-basedAPLP2 Knock-out (Modification: Aplp2: Knock-Out)Mouse (C57BL/6J)--Aplp2APOE gene-basedAPOE2 Knock-in (Modification: APOE: Knock-In)Mouse (C57BL/6; 129P2, back- crossed to C57BL/6J--APOEAPOE2 Knock-in, floxed (CureAlz) (Modification: APOE: Knock-In)Mouse (C57BL/6J)--APOEAPOE2 Knock-in (JAX) (Modification: APOE: Knock-In)Mouse (C57BL/6J)--APOEAPOE2 Targeted Replacement (Modification: APOE: Knock-In)Mouse (C57BL/6J)--APOEAPOE3 Knock-in, floxed (CureAlz) (Modification: APOE: Knock-In)Mouse (C57BL/6J)--APOEAPOE3 Knock-in (JAX) (Modification: APOE: Knock-In)Mouse (C57BL/6J)--APOEAPOE3 Knock-in (Lamb) (Modification: APOE: Knock-In)Mouse (C57BL/6; 129P2, back- crossed to C57BL/6J--APOEAPOE3 Targeted Replacement (Modification: APOE: Knock-In)Mouse (129 x C57BL/6; back- crossed to C57BL/6--APOEAPOE4 Knock-in, floxed (CureAlz) (Modification: APOE: Knock-In)Mouse (C57BL/6J)--APOEAPOE4 Knock-in (JAX) (Modification: APOE: Knock-In)Mouse (C57BL/6J)--APOEAPOE4 Knock-in (Lamb) (Modification: APOE: Knock-In)Mouse (C57BL/6; 129P2, back- crossed to C57BL/6J--APOEAPOE4 Targeted Replacement (Modification: APOE: Knock-In)Mouse (129 x C57BL/6; back- crossed to C57BL/6--APOEAPOE4 Knock-out (Modification: APOE: Knock-out)Mouse (129 x C57BL/6; back- crossed to C57BL/6--APOENSE-ApoE3 (Modification: APOE: Transgenic)Mouse (Origin: C57BL/6J; backcrossed with murine APOE-null mice)--APOENSE-ApoE4 (Modification: APOE: Transgenic)Mouse (Origin: C57BL/6J; backcrossed with murine APOE-null mice)--APOEAPP gene basedA7 APP transgenic (Modification: APP: Transgenic)Mouse (C57BL/6J)APP KM670/671NL (Swedish), APP T714I (Austrian)APPAPP23 (Modification: APP: Transgenic)Mouse (C57BL/6)APP KM670/671NL (Swedish)APPAPP-C99 (tg13592) (Modification: APP: Transgenic)Mouse (C57BL/6 x DBA/2)--APPAPPDutch (Modification: APP: Transgenic)Mouse (C57BL/6J)APP E693Q (Dutch)APPAPP E693Δ-Tg (Osaka) (Modification: APP: Transgenic)Mouse (B6C3F1, back-crossed to C57Bl/6)APP E693del (Osaka)APPAPP Knock-in (Modification: APP: Knock-in)Mouse (C57BL/6J)APP KM670/671NL (Swedish), APP V717I (London), APP E693Q (Dutch)APPAPP Knock-in (humanized Aβ) (Modification: APP: Knock-in)Mouse (C57BL/6J)--APPAPP Knock-out (Modification: APP: Knock-out)Mouse (C57BL/6J)--APPAPP NL-F Knock-in (Modification: APP: Knock-in)Mouse (C57BL/6)APP KM670/671NL (Swedish), APP I716F (Iberian)APPAPP NL-G-F Knock-in (Modification: APP: Knock-in)Mouse (C57BL/6)APP KM670/671NL (Swedish), APP I716F (Iberian), APP E693G (Arctic)APPAPPSwe (Modification: APP: Transgenic)Mouse (C57BL/6, DBA/2, crossed to C57BL/6)APP KM670/671NL (Swedish)APPAPP (Swedish) (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish)APPAPPSwe (line C3-3) (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish)APPAPPSwe (line E1-2) (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish)APPAPPSweLon (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish), APP V717I (London)APPAPPSw-NSE (Modification: APP: Transgenic)Mouse (Origin: C57BL/6 x DBA/2)APP KM670/671NL (Swedish)APPAPP(V642I) Knock-in (Modification: APP: Transgenic)Mouse (Origin:C57BL/6 x CBA; chimeric mice breed to CD-1 mice)APP V717I (London)APPAPP(V717I) (Modification: APP: Transgenic)MouseAPP V717I (London)APPArc48 (APPSw/Ind/Arc) (Modification: APP: Transgenic)Mouse (Inbred C57BL/6)APP KM670/671NL (Swedish), APP V717F (Indiana), APP E693G (Arctic)APPArcAβ (Modification: APP: Transgenic)Mouse (Origin: B6D2 F1)APP KM670/671NL (Swedish), APP E693G (Arctic)APPhAbeta-loxP-KI (Modification: APP: Knock-in)Mouse (mixed B6J; B6NJ)--APPJ20 (PDGF-APPSw,Ind) (Modification: APP: Transgenic)Mouse (C57BL/6)APP KM670/671NL (Swedish), APP V717F (Indiana)APPmThy1-hAPP751 (TASD41) (Modification: APP: Transgenic)Mouse (C57BL/6 x DBA)APP KM670/671NL (Swedish), APP V717I (London)APPNSE-APP751 (Modification: APP: Transgenic)Mouse--APPPDAPP (line109) (Modification: APP: Transgenic)Mouse (C57BL/6 x DBA)APP V717F (Indiana)APPPDGF-APPSw, Ind (line J9) (Modification: APP: Transgenic)Mouse (C57BL/6)APP KM670/671NL (Swedish), APP V717F (Indiana)APPPDGF-APP(WT) (line I5) (Modification: APP: Transgenic)Mouse ((C57BL/6 x DBA/2)F2)APP V717F (Indiana)APPPrnp-APP (Modification: APP: Transgenic)Mouse (C57BL/6)--APPrTg9191 (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish), APP V717I (London)APPTAS10 (thy1-APPswe) (Modification: APP: Transgenic)Mouse (Transgene injected into C57BL/6 x C3H oocytes, some backcrossing to C57BL/6)APP KM670/671NL (Swedish)APPTBA42 (Modification: APP: Transgenic)Mouse (C57BL6)--APPTetO-APPSweInd (line 102) (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish), APP V717F (Indiana)APPTetO-APPSweInd (line 107) (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish), APP V717F (Indiana)APPTetO-APPSweInd (line 885) (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish), APP V717F (Indiana)APPTg2576 (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish)APPTg4-42 (Modification: APP: Transgenic)Mouse (C57BL6)--APPTg-APParc (Modification: APP: Transgenic)Mouse (C57BL6/6-CBA)APP E693G (Arctic)APPtg-APPSwe (Modification: APP: Transgenic)Mouse (C57BL/6J)APP KM670/671NL (Swedish)APPTgAPPSwe-KI (Modification: APP: Knock-in)MouseAPP KM670/671NL (Swedish)APPTg-ArcSwe (Modification: APP: Transgenic)Mouse (C57BL/6J)APP KM670/671NL (Swedish), APP E693G (Arctic)APPTgCRND8 (Modification: APP: Transgenic)MouseAPP KM670/671NL (Swedish), APP V717F (Indiana)APPTg-SwDI (APP-Swedish,Dutch,Iowa) (Modification: APP: Transgenic)Mouse (C57BL/6)APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa)APPAPP21 (Modification: APP: Transgenic)Rat (Fischer 344)APP KM670/671NL (Swedish), APP V717F (Indiana)APPApp Knock-in (humanized Aβ) (Modification: App: Knock-in)Rat (Long-Evans)--AppApp Knock-in (humanized Aβ) (Leuven) (Modification: App: Knock-in)Rat (Long-Evans)--AppApp Knock-in (Icelandic mutation and humanized Aβ) (Modification: App: Knock-in)Rat (Long-Evans)APP A673T (Icelandic)AppApp Knock-in (Swedish mutation and humanized Aβ) (Modification: App: Knock-in)Rat (Long-Evans)APP KM670/671NL (Swedish)AppMcGill-R-Thy1-APP (Modification: APP: Transgenic)Rat (HsdBrl:WH Wistar)APP KM670/671NL (Swedish), APP V717F (Indiana)APPATG16L1 gene basedAtg16LΔWD (Modification: Atg16l1: Knock-out)Mouse (Mixed 129, C57BL/6)--Atg16l1BACE1 gene basedBace1 conditional knock-out (adult, whole body) (Vassar) (Modification: Bace1: Conditional Knock-out)Mouse (C57BL6)--Bace1BACE1 conditional knock-out (Hu, Yan) (Modification: Bace1: Conditional Knock-out)
