Abstract

Memory is vital to experiences and related to limbic systems, it is the retention of information over time for the purpose of influencing future action. Memory is the ability to take in information, store it, and recall it at a later time. Information can be viewed as passing through several storage "buffers" of differing capacity and duration. Alzheimer’s disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more toward the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl D-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure.

Keywords

Introduction

Memory is the faculty of the brain by which information is encoded (process often known as Learning), stored, and retrieved when needed. Memory is vital to experiences and related to limbic systems, it is the retention of information over time for influencing future action. Memory is the ability to take in information, store it, and recall it later. In psychology, memory is broken into three stages: encoding, consolidation, storage, and retrieval. Information can be viewed as passing through several storage "buffers" of differing capacity and duration. The hippocampus, thalamic nuclei, and mamillary bodies in providing the neural substrate necessary for acquiring and retaining new information. Alzheimer’s disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. . The pathophysiology of AD is associated with a variety of factors, including the extracellular deposition of ?-amyloid (A?) plaques, accumulation of intracellular neurofibrillary tangles, oxidative neuronal damage, and inflammatory cascades. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more toward the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl D-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief, but fail to achieve a definite cure. Animal models are classical pharmacological models used as a mandatory element in preclinical (toxicological and pharmacological) studies of new drugs.
Memory [1]
Memory is the faculty of the brain by which information is encoded (process often known as Learning), stored, and retrieved when needed.Memory is vital to experiences and related to limbic systems, it is the retention of information over time for influencing future action.
Memory Process  [1]
Figure no:1 Memory Process
1. Encoding
a.    Encoding is the process of getting information into memory. If information or stimuli never are encoded, it will not be remembered. Information can be encoded/changed in three main ways:
b.    Visual (picture)
c.    Acoustic (sound)
d.    Semantic (meaning)
e.    Visual encoding: Information is represented as a picture.           
f.    Acoustic encoding: Information is represented as sounds.          
g.    Semantic encoding: Information is represented by its meaning to you.
2. Consolidation
 Consolidation is the processes of stabilizing a memory trace after the initial acquisition. It may perhaps be thought of part of the process of encoding or of    storage, or it may be considered as a memory process in its own right.
3. Storage
 Long-term storage may be similar to learning—the process by which   information that may be needed again is stored for recall on demand. It is unclear where long-term memory is stored, although there is evidence depicting long-term memory is stored in various parts of the nervous system. Long-term memory is permanent.
4. Recall or retrieval of memory 
 Recall or retrieval of memory refers to the subsequent re-accessing of events or        information from the past, which have been previously encoded and stored in the    brain. In common parlance, it is known as remembering.
TYPE OF MEMORY[1]
 Information can be viewed as passing through several storage "buffers" of differing capacity and duration.
1.    Sensory memory persists for around 250 milliseconds in the visual mode (iconic memory) and 1 to 2 seconds in the auditory mode (echoic memory). 
2.    Immediate (short-term, primary) memory has a duration of around half a minute    and extensive studies indicate a limited capacity of seven (plus or minus two) items for this buffer, whether the items be numbers, names, visually presented items, or   other "units" of information. 
3.    The remote (long-term) memory buffer stores information lasting from months to a lifetime and contains a personal experiences and knowledge about the world. Information passes into this buffer after it has been sufficiently consolidated. Figure no 2 – Types of memory[1]
Neuroanatomy and Neurophysiology of Memory[2]    
Figure 3.-The drawing shows the limbic areas involved in memory: [2]
i.    A, amygdale
ii.    A, anterior thalamic nucleus; 
iii.    CG, cingulate gyrus; 
iv.    Dm, dorsomedial thalamic nucleus;
v.    EC, entorhinal cortex;
vi.    F, fornix; H, hippocampus;
vii.    Hy, hypothalamus; 
viii.    M, mamillary body;
ix.    Th, thalamus.
•    The role of the hippocampus, thalamic nuclei, and mamillary bodies in providing the neural substrate necessary for acquiring and retaining new information . 
•    It is unlikely that these structures in themselves contain specific memories, but in some way, they provide a means to store and to retrieve memories, particularly those that are undergoing consolidation. 
•    •    The most extensively studied of these limbic regions is the hippocampus.    a patient who showeds evere anterograde amnesia following bilateral amygdalo hippocampectomies for seizure control in 1956, a huge volume of research in humans and animals has sought to define the hippocampal role in memory
•    A critical pathway by which information from the cortical association areas reaches the hippocampus is through the entorhinal cortex located at the anterior pole of the Para hippocampus gyrus. 
•    The amygdala, which receives impulses from large cortical, hypothalamic, and basal fore brain areas, has extensive projections to the entorhinal cortex.
•    Cell bodies in layers II and III of the entorhinalcortex receive the majority of these projections and send fibers through the perforant pathway to the dentate gyrus ofthe hippocampus.
•    The dentate granule cells, in turn, send mossy fibers that synapse on apical dendrites ofthe CA3 cells of the hippocampus. Cells of the dentate gyrus appear capable of integrating recently acquired information.
•    Interestingly, in patients with Alzheimer's disease, neurofibrillary tangles develop in the cells of origin of the perforant pathway (layers II and III of entorhinal cortex), and neuritis plaques develop in the outer layer of the dentate gyrus, effectively disconnecting the hippocampus from the association and limbic cortices.
•    •    Further, CAI pyramidal cells, which receive fibers from the CA3 cells and     serve as the major output from the hippocampus, are themselves extensively affected by neurofibrillary tangles.
•    Layer IV of  the entorhinal cortex, which receives a strong projection from the hippocampus and projects to widespread cortical regions, is also damaged.
•    The hippocampus is thus effectively disconnected from its major incoming and outgoing pathways in Alzheimer's disease . 
Figure 4.-The critical hippocampus memory pathways are shown:[2]
1.    The cell body in layer 11 of the entorhinal cortex (EC) projects through the perforant pathway to the outer layer of the dentate gyrus (DG);
2.    A dentate granule cell sends mossy fibers to synapse on a CA3 pyramidal cell; 
3.    The CA3 cell sends an axon to synapse with a CAl pyramidal cell;
4.    The CAl pyramidal cell sends an axon to synapse on a cell in the subiculum; and 
5.    The subiculum cell sends a projection to layer IV of the entorhinal cortex. The dots (stippled area) indicate regions of cell bodies.
Neurotransmitters: [3]
Figure no 5 - Neurotransmitter Effect[3]
1.Acetylcholine:
Acetylcholine is the primary neurotransmitter for neuromuscular control .it is also important in the brain for memory ,attention ,learning and interest.
2.Seretonin:
Seretonin is involved with memory,learning,stress reduction ,anti  anxiety and relaxation.
3.Dopamine:.
Dopamine is important for executive functions,decision making,reward,pleasure,and regulating movement and emotional effect.
4.Nor adrenaline:
Nor adrenaline act to promote attention ,interest/motivation and mood.
5. Glutamate: 
 Glutamate is involved in learning, memory, and the aging brain.
6.GABA (Gamma-Amino Butyric acid)
Gamma-Amino Butyric acid (GABA) It is plays an important role in a person's behavior, cognition and the body's stress response.    
Pathophysiology of Alzheimer’s disease[4]
Figure no 6:formation of Amyloid Fibrils[4]
APP has two distinct metabolic pathways, in which the action of three secretases.
1.    First, the non-amyloid metabolization involves the proteolysis of APP under the action of a-secretase, which produces a soluble fragment known as a-APP and a smaller 83 amino-acids long peptide. This smaller peptide is then further cleaved by g-secretase into two non-amyloidogenic peptides. Amyloid synthesis is impossible in this case because a-secretase cleaves APP in the middle of the fragment that forms the amyloidogenic peptides.
2.    Second, the amyloid metabolization involves the proteolysis of APP under the action of ?-secretase. These results in the production of another soluble fragment called ?-APP and a 91 amino-acid long peptide that is further cleaved by ?-secretase, releasing amyloidogenic peptides (Ab40, Ab42, and Ab43).
Figure no 7: Metabolic Pathway and action of three secretases.[4]
Types of Pathophysiology[5]
With pathophysiology of AD, debate goes back to the Alzheimer’s time 1907 when he observed the neuropathological features of the disease i.e. amyloidal plaques and hyperphosphorylated NFTs (Neuro Fibrillary Tangles). Several hypotheses have been put forward on the basis of the various causative factors in order to explain this multifactorial  disorder such as the,
1.    Amyloid Cascade Hypothesis
2.    Tau hypothesis
3.    Inflammation hypothesis
Amyloid Cascade Hypothesis[5]          
The amyloid hypothesis states that amyloid plaques formed by aggregates of A? peptide generated by the proteolytic cleavages of APP are central to AD pathology.  APP belongs to a large family of type I membrane proteins with a large extracellular domain and a short cytoplasmic region derived by differential splicing of a single gene transript located on the long arm of chromosome 21. The predominant isoforms, APP770, APP751, and APP695 are expressed with some tissue specificity. The two longer isoforms of APP, APP751 and APP770, contain a 56 amino acid long ectodomain.APP is cleaved throughout the Golgi complex by O-glycosylation. The major processing pathway of APP is nonamyloidogenic, the cleavage necessitated by ?-secretase occurring between Lys16 and Leu17 within the A? domain preventing the formation of Abpeptides. During this cleavage, a soluble ectodomain of APP (sAPP?) is released and a 10-kDa C-terminal fragment (p3CT) remains within the membrane.   The soluble peptide derived from APP, sAPP? may have neuroprotective roles. Atleast 30% of APP is processed by this pathway.A? generation from APP occurs via a two-step proteolytic process involving ?- and ?-secretases. The ?-site APP cleaving enzyme (BACE1), first cleaves APP to generate a membrane bound soluble C-terminal fragment. A subsequent cleavage of the C-terminal fragment by the ?-secretase activity further generates A?40 and A?42.  Types of peptide could be found in amyloid plaques, but A?42 is apparently more directly neurotoxic and has a greater propensity to aggregate. A pathway by which APP is cleaved is called amyloidogenic pathway.  Under normal conditions, about 90% of secreted A? peptides are A?40, which is asoluble form of the peptide that only slowly converts to an insoluble ?-sheet configuration and thus can be eliminated from the brain. In contrast, about 10% of secreted A? peptides are A?42 , species that are highly fibrillogenic and deposited early in individuals with AD and Down's syndrome. Intracellular assembly states of A? are monomers, oligomers, protofibrils, and fibrils.  The monomeric species are not pathological, however the nucleation dependent fibril formation related to protein misfolding makes the A? toxic. The oligomeric and protofibrillar species may facilitate tau hyperphosphorylation, disruption of proteasome and mitochondria function, dysregulation of calcium homeostasis, synaptic failure, and cognitive dysfunction.   
 Figure 8: Amyloid cascade hypothesis [5]
Tauhypothesis[5]
The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs. Tau protein is a highly soluble microtubule-associated protein (MAP). Through its isoforms and phosphorylation tau protein interacts with tubulin to stabilize microtubule assembly. Tau proteins constitute a family of six isoforms with the range from 352-441 amino acids. The longest isoform in the CNS has four repeats (R1, R2, R3, and R4) and two inserts (441 amino acids total), whereas the shortest isoform has three repeats (R1, R3, and R4) and no insert (52 amino acids total). All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments .Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action, or exposure to polyanions, such as glycosaminoglycans.  Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAP 1(microtubule-associated protein1), MAP 2, and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death. 
Figure 9: Tau hypothesis[5]
Inflammatory Hypothesis [5]
Microglia, astrocytes and possibly to a lesser extent the neurons are involved in the inflammatory process in AD. A? can activate microglia which leads to an increase in cell surface expression of major histocompatibility complex II (MHC II) along with increased secretion of the pro-inflammatory cytokines interleukin-1? (IL-1?), interleukin-6 (IL-6), and tumor necrosis factor ? (TNF ?) as well as the chemokines- interleukin-8 (IL-8), macrophage inflammatory protein-1 ? (MIP-1 ?), and monocyte chemo-attractant protein-1.  A? also induces a phagocytic response in microglia and expression of nitric oxide synthase (NOS) resulting in neuronal damage. Microglia may also play a role in the degradation of A? by the release of insulin degrading enzyme. Astrocytes also cluster at sites of A? deposits and secrete interleukins, prostaglandins, leukotrienes, thromboxanes, coagulation factors, and protease inhibitors. Neurons themselves are able to express significantly higher levels of classical pathway complement and pro-inflammatory products that trigger inflammatory processes. Further, the complement system, cytokines, chemokines, and acute phase proteins (especially pentraxins) contribute to the inflammatory response in AD. The neuroinflammation as a primary cause or secondary effect in Alzheimerogenesis is a chicken and egg question.
Fig No: 10    Comparison between Normal neuron and Alzheimer Neuron[6]
Neurotransmitters in Alzheimer’s disease[7] 
Neurotransmitter involve in Alzheimer’s disease
1.    Acetylcholine
2.    Dopamine
3.    Norepinephrine
4.    Glutamate
5.    Serotonin
Acetylcholine
Basal forebrain cholinergic cell loss is a consistent feature of AD. Impaired cortical cholinergic neurotransmission contributes to A? pathology and increases phosphorylation of tau protein. Selective activation of M1-M3-but not M2- M4-mAChR (muscarinic acetylcholine receptor) increases sAPP? secretion and decreases total A? formation.The mAChRs mediate their effects on APP processing through Activation of the phosphatidyl inositol-signaling pathway and probably via the tyrosine kinase MAP (mitogen-activated protein) kinase pathway. In contrast, BACE1 expression was downregulated by activation of M2-mAChR and protein kinase A-mediated pathways. Nicotine through action on nicotinic nAChR (nicotinic acetyl choline receptor) has also been observed to modulate APP processing by favoring the Non-amyloidogenic pathway. Nicotine also causes inhibition of A? fibril formation and disruption of preformed A? fibrils. A? decreases the intracellular acetylcholine concentration and impairs M1 receptors. By direct binding with high affinity to nAChR, in particular to the ?7 subtype, A? may disrupt the receptor function Activation of nAChR results in a significant increase in tau phosphorylation, whereas mAChR activation may prevent tau phosphorylation.
Dopamine
There is evidence that micromolar concentrations of dopamine or L-dopa are sufficient to significantly inhibit fibril formation or disaggregate existing fibrils of A?. D1 receptor seems to play a more prominent role in mediating plasticity In addition, specific aspects of cognitive function, including spatial learning and memory processes and D1 agonists are being tried for improving cognition in AD.
Norepinephrine
There is loss of locus coeruleus (LC) neurons in AD. Norepinephrine in several brain areas is reduced and this reduction is mostly limited to patients with an earlier age of and greater severity of intellectual deterioration. There is loss of ?-2 receptor function in AD. Findings also show that an intact noradrenergic system is a prerequisite for the integrity of at least some central cholinergic functions. Therefore, multiple lines of evidence implicate norepinephrine in AD. 
Glutamate
Malfunctions in components of the glutamate–glutamine cycle could result in a self-perpetuating neuronal death cascade and glutamatergic excitotoxicity.Chronic neuronal insults may lead to the activation of extra-synaptic NMDA (N-methyl D aspartate) receptors. This interacts with ‘fyn’ [src (proto oncogenic) family tyrosine kinase] through two scaffolding proteins, DLG4 (Discs large homolog 4, involved in  Anchoring synaptic proteins) and GNB2L1 (Guanine nucleotide binding protein). Mechanisms of DLG4 association and GNB2L1 dissociation from Fyn contributeto chronic NMDAR hyperactivity in AD. Fyn further activates extra-synaptic NMDA
(NR2B subunit) causing continued Ca+two influxes into the cytoplasm. High intracellular Ca+two lead to mitochondrial dysfunction. Chronic over-activation of extra-synaptic NMDAR sends a CREB (cyclic AMP response element binding protein) shut-off signal whereby levels of phospho-CREB decline. This leads to decreased production Of pro-survival signals like BDNF, (brain derived neurotrophic factor). All these events lead to cellular dysfunction and neuronal death over a period. A? via stimulation of nitric oxide enhances glutamate release. A? also inhibits glial uptake of glutamate and thus contributes to glutamatergic excitotoxicity.
Serotonin
Serotoninergic involvement in AD is evidenced by the observations that
1.    AD is characterized by CSF alteration of 5HT and 5HIAA
2.    Loss of 5HT synthesizing neurons and 5HT receptors in AD
3.    The presence of 5 HT polymorphisms inAD and
4.    The improvement especially of agitation and other behavioral symptoms of AD with serotonergic agents.
Treatment[8]
Fig no 11 ;types of drug [8]
FDA-approved treatments for Alzheimer’s [9]
1.    While there is no cure for Alzheimer’s disease, there are five prescription drugs currently approved by the Food and Drug Administration (FDA and rivastigmine  are from a class of drugs called “cholinesterase inhibitors.”) to treat its symptoms.Three of the five available medications donepezil, galantamine 
2.    These drugs prevent the breakdown of a chemical messenger in the brain that is important for learning and memory.
3.    The fourth drug, memantine, regulates the activity of a different chemical messenger in the brain that is also important for learning and memory. Both types of drugs help manage symptoms but work in different ways.
4.    The fifth medication is a combination of one of the cholinesterase inhibitors (donepezil) with memantine. 
5.    That available treatment options can help individuals living with the disease and their caregivers to cope with symptoms and improve quality of life. 
Cholinesterase inhibitors: [9]
Cholinesterase inhibitors are prescribed to treat symptoms related to memory, thinking, language, judgment, and other thought processes. 
Three different cholinesterase inhibitors are commonly prescribed:  
1.    Donepezil -marketed under the brand name Aricept®, which is approved to treat all stages    of   Alzheimer’s disease.  
2.    Galantamine -Razadyne®, approved for mild-to-moderate stages. 
3.    Rivastigmine -Exelon®, approved for mild-to-moderate Alzheimer’s. 
Mechanism of cholinesterase inhibitors :
1.    Cholinesterase inhibitors work by increasing levels of acetylcholine, a chemical messenger involved in memory, judgment and other thought processes. 
2.    Certain brain cells release acetylcholine, which helps deliver messages to other cells. 
3.    After a message reaches the receiving cell, various other chemicals, including an enzyme called acetylcholinesterase, break acetylcholine down so it can be recycled.  4. Alzheimer’s disease damages or destroys cells that produce and use       acetylcholine,    thereby reducing the amount available to carry messages. 
4.    A cholinesterase inhibitor slows the breakdown of acetylcholine by blocking the activity of acetylcholinesterase.    
5.    By maintaining acetylcholine levels, the drug may help compensate for the          loss of functioning brain cells. Cholinesterase inhibitors seem to offer other benefits, as well. 
6.    For example, galantamine appears to stimulate the release of acetylcholine and strengthen the way certain message-receiving nerve cells respond to it.
7.    Rivastigmine may block the activity of another enzyme involved in breaking down of acetylcholine.
8.    Cholinesterase inhibitors cannot reverse Alzheimer’s and will not stop the underlying destruction of nerve cells. Consequently, their ability to improve symptoms eventually declines as brain cell damage progresses.
Benefits of cholinesterase inhibitors:
1.    In clinical trials of all three cholinesterase inhibitors, people taking the medications performed better on memory and thinking tests than those taking a placebo, or inactive substance. However, the degree of improvement was small.
2.    In terms of overall effect, cholinesterase inhibitors may delay or slow worsening of symptoms. The effectiveness of cholinesterase inhibitors, as well, as how long they are effective, varies from person to person. 
3.    There is no evidence that combining the three drugs would be more helpful than taking any one of them. In fact, combining them would likely result in greater frequency of side effects.
4.    There is some evidence that individuals with moderate-to severe Alzheimer is who are taking a cholinesterase inhibitor might benefit by also taking memantine.
5.    The makers of Aricept (donepezil) released a 23 mg extended-release tablet of the medication intended for individuals with moderate-to-severe Alzheimer’s who have been taking the more common 10 mg dose for at least three months.
6.    6.  These individuals may have a better result with the extended-release form of        Aricept, although both the extended-release and original forms can cause similar    side effects. Ask your doctor whether the extended-release forms may be a better     option for the person with dementia.
Common side effects of cholinesterase inhibitors:
 Cholinesterase inhibitors are generally well tolerated. If side effects occur, they    commonly include 
1.    Nausea, 
2.    Vomiting,
3.    Loss Of Appetite And 
4.    Increased Frequency Of Bowel Movements. 
It is strongly recommended that a physician who is experienced in using these medications monitor patients who are taking them and that the recommended guidelines are strictly observed.
NMDA  antagonist[9]
Memantine
Memantine (Namenda®) is prescribed to improve memory, attention, reason, language, and the ability to perform simple tasks. It was the first Alzheimer’s drug of the NMDA receptor antagonist type approved in the United States. It is used to treat moderate-to-severe Alzheimer’s.
Mechanism of memantine 
1.    Memantine appears to work by regulating the activity of glutamate, a chemical involved in information processing, storage and retrieval. 
2.    Glutamate plays an essential role in learning and memory by triggering NMDA receptors to let a controlled amount of calcium into a nerve cell.
3.    The calcium helps create the chemical environment required for information storage. Excess glutamate, on the other hand, overstimulates NMDA receptors so that they allow too much calcium into the nerve cells. 
4.    That leads to disruption and death of cells. Memantine may protect cells against excess glutamate by partially blocking NMDA receptors.
 Benefits of memantine
1.    One clinical study showed that people taking memantine showed a small but statistically significant improvement in their mental function and ability to perform daily activities.
2.    But study participants with the lowest cognitive functioning showed no improvement on either daily activities or overall function. 
3.    Another study randomly assigned participants to receive either 10 mg of memantine twice a day or a placebo in addition to donepezil (Aricept), a cholinesterase inhibitor. 
4.    Those receiving memantine showed a statistically significant benefit in mental functioning and performing daily activities, while participants taking donepezil plus placebo continued to decline.
Side effects of memantine
Adverse side effects include
1.    Headache, 
2.    Constipation,
3.    Confusion,
4.    Dizziness. 
Combination of donepezil and memantine
1.Namzaric®, a combination of donepezil and memantine, was approved by the FDA for the treatment of moderate-to-severe Alzheimer’s in people who are taking donepezil hydrochloride 10 mg.
2. Namzaric may cause serious side effects, including: 
a    Muscle problems in patients given anesthesia.
b    Slow heartbeat and fainting:
c    Increased stomach acid: This raises the chance of ulcers and bleeding,
d    Nausea and vomiting. 
e    Difficulty passing urine.
f    Seizures.  
g    Worsening of lung problems in people with asthma or other lung disease.
3. Individuals taking Namzaric may see an improvement in cognition and overall mental function, and a temporary slowdown in the worsening of symptoms. 4. However, there is no evidence that Namzaric prevents or slows the underlying disease process in patients with Alzheimer's disease.
Recent advances in treatment of AD [11]
Different types of therapy involve in treatment of AD as following:
1.    Anti-amyloid therapy
2.    2.????-Secretase (BACE1) inhibitor 
3.    3.?-Secretase inhibitors (GSI) and modulators (GSM)
4.    Kinase inhibitors 
5.    Therapy for mitochondrial dysfunction 
6.    Anticholinergic therapy 
1. Anti-amyloid therapy [11]
Anti-amyloid therapy involves the uses of drugs with a different mechanism of actions: 
a.    enhance the clearance of A?;
b.    Prevent the production of A?; or
c.    Inhibit the accumulation of A?. 
Active and passive immunization results in decreased levels of intracerebral A? burden by inducing humoral reaction against the A? peptide leading to its clearance from the brain .[9]
2.????-Secretase (BACE1) inhibitor 
Beta-site APP-cleaving enzyme 1 (BACE1) is a protease responsible for cleavage of APP, resulting in generation of assembly of neurotoxic irregular A????. Nuclear peroxisome proliferator activated receptor gamma (PPAR????) functions as a transcription factor which regulates gene expression, promotes microglia-mediated A????endocytosis. In addition, it reduces inflammation response and causes decreased cytokine excretion. Thiazolidinedione can induce PPAR???? to inhibit ????-secretase and stimulate ubiquitination to worsen amyloid burden. It has been also reported that PPAR???????? agonist i.e. thiazolidinedione derivatives like rosiglitazone and pioglitazone worsens AD neuropathology by reducing insulin sensitivity which helps in A???? proteolysis.
3.?-Secretase inhibitors (GSI) and modulators (GSM)
 ?-secretase is a transmembrane protease responsible for cleavage of amyloid precursor protein (APP) to produce A?. Different GSIs such as DAPT, L685458 andMRK-560 have been recently developed. While different (GSM) such as avagacestat (BMS-708163), begacestat, and NIC5-15 are under clinical trials.
4. Kinase inhibitors 
The first class of tau inhibitors, which helps in targeting tau phosphorylation and reduces tau phosphorylation by decreasing the activity of kinase enzyme. Interaction between glycogen synthase kinase 3 beta (GSK3????????) and protein phosphate 2 (PP2A) augments tau hyper phosphorylation and NFT generation. Lithium, valproate, NP-031112 (NP-12) and epothilone D (BMS-241027) decreases tau phosphorylation and prevent reversed features of tauopathy.    
5. Therapy for mitochondrial dysfunction 
Latrepirdine (DIMEBON), an antihistamine that preserves mitochondrial structure and function and protects against A???? induced apoptosis is under investigation. Its combination with donepezil is also under investigation. AC-1204 is considered to improve mitochondrial metabolism by inducing chronic ketosis, thereby releasing regional cerebral hypometabolism presented in early Alzheimer’s disease, and this agent is under investigation.
6. Anticholinergic therapy 
Anticholinergic therapy includes administration of cholinesterase inhibitors to treat the cholinergic deficit associated with AD. The drugs include tacrine (COGNEXS), donepezil (ARICEPTS), rivastigmine (EXELON), and galantamine (REMINYLS).
7. Models for Evaluations Of Antiamnesic Activity :[13]
In-Vitro Methods 
 There are two types of methods, which are as follows;
1.    In vitro inhibition of acetylcholine esterase activity in rat striatum 
2.    In vitro inhibition of butyrylcholine esterase activity in human serum  
In-Vivo Methods
There are four methods, which are as follows:
1.    Inhibitory (passive) avoidance            
2.    Active avoidance 
3.    Discrimination learning                       
4.    Condition responses
Step Down Model
Figure no 12 . Step Down Model:[14]
 PURPOSE AND RATIONALE
 An animal (mouse and rat) in an open spends most of the time close to the walls and in corners. When placed on elevated platform in the centre of a rectangular compartment, it steps down almost immediately to the floor to explore the enclosure and to approach the wall.
Procedure[13]
Mice or rats of either sex are used. A rectangular box with electrifiable grid floor 35cm fits over the block. The grid floor connected to the shock device. The experiment is performed in the different ways; 1) Familiarization- 
animal is placed on platform; release after raising the cylinder, latency to descend is measured. 2) Learning- 
immediately after descend, unavoidable foot shock is applied (50Hz; 1.5mA) animal return to home 3) Retention-
 after 24hrs, learning trial animal again placed on platform, step down latency is measured. 
OBSERVATION:
 The time of descent during the learning phase and the time during the retention test are measured. 
INFERENCE: 
The prolongation of step down latency is defined as learning.
Step through model[15]
Figure no 13 . Step through model [15]
PURPOSE AND RATIONALE[15]
This test uses the normal behavior of mice and rats. These animal avoid bright light and prefer dim illumination.When placed in to the bright illuminated space connected to a dark enclosure, they rapidly enter into the dark compartment and remain there.It is widely used in the testing the effects of memory active compounds.
PROCEDURE
1.    Mice and rats of either sex used, the test apparatus consist of small chamber connected to a larger dark chamber via guillotine door.  
2.    Small chamber light up with (7W/12V) bulb, animal is placed in an illuminated compartment at max distance from guillotine door; the latency to enter in to dark compartment is measured. 
3.    Immediately after entry in to dark compartment the door is shut automatically and unavoidable foot shock is given (1ma; one mice) the animal is quickly removed from apparatus and return to home cage.
4.    Test is repeated, the cut off time on day2 is 300 or 600.
OBSERVATION
The time to step-through during the learning phase is measured and the time during retention test is measured.
INFERENCE
An increase of the step-through latency is defined as learning
Runway avoidance model[16]
Figure no 14 ; Runway avoidance model[16]
PURPOSE AND RATIONALE-
The shock can avoided when the safe area is reached within the time allocated.
PROCEDURE-
1.    Mice or rats either used, the same box as used in the step-through model can be used, the apparatus is uniformly illuminated by overhead light source, foot shock is employed by the same source as in step through avoidance, animal is allowed to explore the whole apparatus for 5 min, the guillotine door is then closed and animal is placed in light starting area.
2.    After 10s the conditioned stimulus is applied and door is simultaneously opened. Shock is turned on after five. 3. The conditioned stimulus contineous until the animal reaches the safe area. It is left 50-70 s before return to the same area again, the procedure start again. On the next the procedure is repeated until same learning criteria is reached.
3.    The time needed to reach safe is measured.
OBSERVATIONS
The time the animal needs to reach the safe area on both days is measured.
INFERENCE
No of errors is also recorded.                                                 
Spatial habituation learning [17]
Figure no 15 Spatial habituation learning[17]
 PURPOSE AND RATIONALE
1.    Spatial habituation learning is defined as a decrement in reactivity to a novel environment after the repeated exposure to that now familiar environment. 
2.    This reduction in exploratory behavior during re-exposure is interpreted in terms of remembering of the specific physical characteristics of the environment.
3.    The test can be used to examine short-term spatial memory or long term spatial memory.
PROCEDURE
1.    The open field apparatus is rectangular chamber, made of painted red or grey PVC. A25W red or green light bulb is placed directly above. 2. The prior to each trial the apparatus is swept out with water containing 0.1?etic acid; housing room and testing room location are separated.
2.    The digitized image of the path taken by each animal is stored and analyzed post hoc with semi-automated analysis system.
3.    The rodents are placed on the centre or in the corner of the open field for 5-10 min sessions.
OBSERVATION
The exploratory behavior is registered are Rearings or vertical activiy; the number of time animal standing on its hind legs with forelegs in the air. 
INFERENCE
The duration of single rearings as a measure of non-selective attentation Locomotion or horizontal activity.
Studies in aged monkeys[18]
PURPOSE AND RATIONALE-
1.    Nonhuman primates (NP) have the closet taxonomic relationship to human, sharing very morphologic and physiologic similarities in the CNS. 2. These similarities increases the likelihood that studies in aged nonhuman primates will provide the information about drugs that is relevant to humans. 3.Nonhuman primates offers the additional advantage for neurobehavioral animal models of aging in that many of the behavioral processes thought to be affected by aging can be studied easily in nonhuman primates.
Procedure 
1.    The special apparatus developed for primate model named is Automated General Experimental Device (AGED)
2.    2.The AGED is much automated computerized system, whose prominent feature consists of 3*3 matrixes of stimulus responses (SR) panels.
3.    Each SR panel is joint directly in front of the reinforcement well so that when panel is pushed, a red switched is magnetically activated and reinforcement well is exposed. 4. Both color and pattern stimuli can be projected on to the SR panels.   5. The stimulus observation window is equipped with a photocell and an infrared light source to detect when monkey’s head is oriented towards the stimuli.
OBSERVATIONS
The monkey must remember the stimulus location to get reinforcement. 
INFENENCE
Number of correct answer will be counted as well as the time until the monkey answers correctly.
CONCLUSION
Memory is the ability to take in information, store it, and recall it later.  Information can be viewed as passing through several storage "buffers" of differing capacity and duration. Memory loss in adult age leads to a dementia. Alzheimer’s disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Several hypotheses have been put forward on the basis of the various causative factors in order to explain this  multifactorial disorder such as the, amyloid Cascade Hypothesis , tau hypothesis , inflammation hypothesis. While there is no cure for Alzheimer’s disease, there are five prescription drugs currently approved by the Food and Drug Administration (FDA) to treat its symptoms. But these drugs are associated with severe side effect which limit their use and hence various new drugs acting at different targets in pathological steps of  Alzheimer’s disease are being  evaluated currently. Viz, Anti-amyloid therapy, ????-Secretase (BACE1) inhibitor, ?-Secretase inhibitors (GSI) and modulators (GSM), Kinase inhibitors, therapy for mitochondrial dysfunction, Anticholinergic therapy that available treatment options can help individuals living with the disease and their caregivers to cope with symptoms and improve quality of life. It is clear that further study of the neurobiology of Alzheimer’s disease remains important as a means of providing innovative targets for Alzheimer’s therapies. In addition, current progress in biology offers corporation of new findings into animal models of Alzheimer’s disease.
ACKNOWLEDGMENTS
It is a genuine pleasure to express my deep sense of thanks and gratitude to many mentor and guide Dr .Priti P Patel , Department of pharmacology, Dr. L. H. Hiranandani college of pharmacy, Ulhasnagar. Her dedication and keen interest, overwhelming attitude to help her student had been solely and mainly responsible for completing my work.  Her timely advise, meticulous scrutiny, scholarly advice and scientific approach have help me to a very great extent to accomplish this task.
I also thank our respected principle Dr. Parag Gide sir, Dr. L.H. Hiranandani college of pharmacy, Ulhasnagar and H(S)NC Board for providing me an opportunity to prevent this seminar. As well as for their generous consideration, facilities support and encouragement to keep my moral high for the seminar work. I have taken efforts in this project. However, it would not have been possible without the kind support and help of many individuals. I would like to extend my sincere thanks to all of them
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