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Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator

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UCSD team targeting new stress pathway in Alzheimer’s program

By John Carroll

has long been one of the most frustrating targets in R&D. Despite repeated assurances from rival camps that toxic loads of amyloid beta and tau are likely causes of the diseases, no one is quite sure what is going on and clinical failures are routine. But investigators at UC San Diego School of Medicine say they have been garnering some preclinical clues that would suggest there could be a new pathway to follow in the clinic.

Following the idea that the brain’s stress signaling circuitry may play a role in the development of the disease, the UCSD group centered on a hormone called corticotropin-releasing factor. CRF is a neuropeptide that triggers the behavioral and biologic responses to stress, which UC says has been associated with worsening cognition as well as the alteration of tau and the creation of a-beta.

The team found a way to block the CRF receptor in mouse models for the disease with an anti-anxiety and IBS drug called R121919. Cellular damage was reduced, the scientists say, while the behavioral changes associated with the disease were also avoided in the mice.

“The novelty of this study is two-fold: We used a preclinical prevention paradigm of a CRF-antagonist (a drug that blocks the CRF receptor in brain cells) called R121919 in a well-established AD model–and we did so in a way that draws upon our experience in human trials,” said Robert Rissman, an assistant professor in the Department of Neurosciences and Biomarker Core Director for the Alzheimer’s Disease Cooperative Study, in a release. “We found that R121919 antagonism of CRF-receptor-1 prevented onset of cognitive impairment and synaptic/dendritic loss in AD mice.”

The group followed up by saying that R121919 appeared to be a safe way to hit the stress pathway, but that it was unlikely that they could repurpose the drug specifically for Alzheimer’s. Now the team plans to search for new drugs that can do the same thing, with an eye to getting into the clinic.

“Rissman’s prior work demonstrated that CRF and its receptors are integrally involved in changes in another AD hallmark, tau phosphorylation,” said Dr. William Mobley, chair of the Department of Neurosciences and interim co-director of the Alzheimer’s Disease Cooperative Study at UC San Diego, in the release. “This new study extends those original mechanistic findings to the amyloid pathway and preservation of cellular and synaptic connections. Work like this is an excellent example of UC San Diego’s bench-to-bedside legacy, whereby we can quickly move our basic science findings into the clinic for testing.”

Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer’s disease

Preclinical study points to GPR3 as a potential target for Alzheimer’s

The role of G protein-coupled receptors in the pathology of Alzheimer’s disease
Amantha Thathiah and Bart De Strooper
Nature Reviews Feb 2011; 12: 73-87

Abstract | G protein-coupled receptors (GPCRs) are involved in numerous key neurotransmitter systems in the brain that are disrupted in Alzheimer’s disease (AD). GPCRs also directly influence the amyloid cascade through modulation of the α-, β- and γ-secretases, proteolysis of the amyloid precursor protein (APP), and regulation of amyloid-β degradation. Additionally, amyloid-β has been shown to perturb GPCR function. Emerging insights into the mechanistic link between GPCRs and AD highlight the potential of this class of receptors as a therapeutic target for AD.

Figure 1 | Modulation of APP processing by GPcrs. Cleavage of amyloid precursor protein (APP) by α-secretase generates the soluble amino-terminal ectodomain of APP (sAPPα) and the carboxy-terminal fragment C83. Subsequent cleavage of C83 by the γ-secretase complex yields the APP intracellular domain (AICD) and a short fragment termed p3. Several G protein-coupled receptors (GPCRs), including muscarinic, metabotropic and serotonergic receptors modulate α-secretase-mediated proteolysis. Alternatively, cleavage of APP by β-secretase generates sAPPβ and the C-terminal fragment C99. Subsequent cleavage of C99 by the γ-secretase complex yields the AICD and the amyloid-β peptide. Of the GPCRs that regulate this processing, the δ-opioid receptor (DOR) and the adensoine A2A receptor (A2AR) have been shown to modulate β-secretase-mediated cleavage of APP, whereas the β2 adrenergic receptor (β2-AR), G protein-coupled receptor 3 (GPR3), and CXC-chemokine receptor 2 (CXCR2) have been shown to modulate γ-secretasemediated cleavage of C99 or C83. Aβ, amyloid-β; ADAM, a disintegrin and metalloproteinase; BACE1, β-site APP-converting enzyme 1; CRHR1, corticotrophinreleasing hormone (CRH) receptor type I; 5-HT, 5-hydroxytryptamine (serotonin); mAChR, muscarinic acetylcholine receptor; mGluR, metabotropic glutamate receptor; PAC1R, pituitary adenylate cyclase 1 receptor.

Box 1 | The cholinergic and amyloid cascade hypotheses
The amyloid cascade hypothesis The amyloid cascade hypothesis postulates that gradual changes in the metabolism and aggregation of amyloid-β initiates a cascade of neuronal and inflammatory injury that culminates in extensive neuronal dysfunction and cell death associated with neurotransmitter deficits and dementia145,146. The cholinergic hypothesis The cholinergic hypothesis posits that a dysfunction in acetylcholine (ACh)-containing neurons substantially contributes to the cognitive decline observed in Alzheimer’s disease (AD)147. This is based on the observation that cholinergic transmission has a fundamental role in cognition and is disrupted in patients with AD148,149. convergence of the amyloid cascade and cholinergic hypotheses ACh is a key neurotransmitter involved in learning and memory150 that binds to distinct receptor subtypes in the brain: nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChRs). Nicotinic neurotransmission is implicated in the pathogenesis of AD (TABle 1). Additional evidence suggests that the major mAChR subtypes involved in AD are the postsynaptic M1 mAChRs, which mediate the effects of ACh, and the presynaptic M2 mAChRs, which inhibit ACh release151, 152. Amyloid-β deposition may contribute to the cholinergic dysfunction in AD by decreasing the release of presynaptic ACh and impairing the coupling of postsynaptic M1 mAChRs with G proteins. This leads to decreased signal transduction, impairments in cognition, a reduction in the levels of amyloid precursor protein (APP), the generation of more neurotoxic amyloid-β and a further decrease in ACh release111. Genetic ablation of the M1 mAChR in a transgenic mouse model of AD decreases the production of the soluble amino-terminal ectodomain of APP (sAPPα), increases amyloid-β generation and exacerbates the amyloid plaque pathology28, supporting the development of M1-selective agonists. In addition, M1 mAChR activation reduces tau phosphorylation27,153 and alleviates hippocampus-dependent memory impairments27, making M1 mAChRs a compelling therapeutic target for AD. Furthermore, receptor subtype specificity will be of key importance as M2 and M4 mAChRs seem to inhibit sAPPα release and potentially aggravate amyloid-β generation28,30, and activation of nAChRs exacerbates the tau pathology154.

Figure 2 | GPcr signalling and the α-secretase pathway. G protein-coupled receptors (GPCRs) exert their multiple functions through a complex network of intracellular signalling pathways. Ligand-bound GPCRs activate heterotrimeric G proteins, inducing the exchange of GDP for GTP and the formation of a GTP-bound Gα subunit and the release of a Gβγ dimer. The G protein subunits then activate specific secondary effector molecules, such as adenylyl cyclase (AC), phospholipase C (PLC) and phospholipase A2 (PLA2), leading to the generation of secondary messengers and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Janus kinase (JAK) and phophoinositide 3-kinase (PI3K), and modulation of the α-secretase pathway. In the case of the M1 muscarinic acetylcholine receptor (M1 mAChR), the group I metabotropic glutamate receptors (mGluRs) and the 5-hydroxytryptamine receptors 5-HT2A/2CR and 5-HT4R, agonist stimulation leads to an increase in soluble amyloid precursor protein (sAPP) release, a decrease in amyloid-β (Aβ) generation, a decrease in tau phosphorylation and/or an alleviation of the cognitive deficits in a mouse model of Alzheimer’s disease (AD). Conversely, agonist stimulation of the Group II mGluRs leads to an increase in amyloid-β42 generation, tau phosphorylation and an exacerbation of the cognitive deficits in an AD mouse model. In the case of the 5-HT6 receptor (5-HT6R), antagonism of the receptor leads to an improvement in cognition. Solid arrows represent direct signalling pathways and dashed arrows represent signalling via intermediates that are not shown. ACh, acetylcholine; ADAM, a disintegrin and metalloproteinase; cAMP, cyclic AMP; GSK3β, glycogen synthase kinase 3β; NMDAR, NMDA receptor; PKC, protein kinase C; sAPPα, soluble amino-terminal ectodomain of APP; STAT, signal transducer and activator of transcription.

Pituitary adenylate cyclase 1 receptor. The pituitary adenylate cyclase 1 receptor (PAC1R) is a GPCR that is stimulated by the neuropeptide pituitary adenylate cyclase­activating polypeptide (PACAP). The receptor is primarily localized to the hypothalamus but is also expressed in the cerebral cortex and hippocampus72, areas of the human brain affected by AD. The major form of PACAP, composed of 38 amino acids (PACAP38), has been show to improve memory in rats73. Together with a C­terminal truncated form, PACAP27, it stimulates an increase in sAPPα release74. This effect is blocked by a broad­spectrum metalloprotease inhibitor and by an ADAM10­specific inhibitor, GI254023X74. Thus, stimulation of PAC1R enhances α­secretase activity. Although the molecular mechanism of this effect has not been elucidated, neuropeptide hormones such as PACAP27 and PACAP38 display a high flux rate across the blood–brain barrier (bbb)75, which should permit the in vivo examination of the effect of PACAP in a transgenic mouse model of AD.
Regulation of b-secretase The β­secretase bACE1 (β­site APP­converting enzyme 1), is a type I transmembrane aspartyl protease that is active at low pH and is predominantly localized in acidic intracellular compartments, such as endosomes and the trans­Golgi network. Cleavage of APP by bACE1 generates a soluble n­terminal ectodomain of APP (sAPPβ) and the n terminus of amyloid­β. Subsequent cleavage of the membrane­bound C­terminal fragment C99 by the γ­secretase liberates the amyloid­β peptide species (FIG. 1). bACE1 is abundantly expressed in neurons in the brain. Bace1–/– mice are viable and fertile, facilitating the study of the role of this enzyme in AD. bACE1 deficiency in an AD mouse model abrogates amyloid­β generation, amyloid pathology, electrophysiological dysfunction and cognitive deficits, implying that therapeutic inhibition of bACE1 would decrease generation of all amyloid­β species. However, Bace1–/– mice display phenotypic abnormalities that are related to the processing of additional proteins by bACE1, suggesting that therapeutic inhibition of bACE1 could have adverse side effects (reviewed in ReFS 76,77). nevertheless, bACE1 is arguably the primary therapeutic target to deter amyloid­β generation. Detailed structural analysis of bACE1 has led to the discovery of many transition state­based inhibitors with activity in the low nanomolar range, although the in vivo efficacy of these compounds is limited because most of them do not penetrate the bbb or are actively exported from the brain by P­glycoprotein. Recent evidence suggests that GPCRs such as the δ­opioid receptor (DOR)78 could provide a therapeutic opportunity to modulate bACE1 and amyloid­β generation .
δ‑ and μ‑opioid receptors. The opioid receptors, which play important parts in learning and memory, are deregulated in specific regions of the AD brain79. There is evidence to suggest that the DOR, together with the β2 adrenergic receptor (β2­AR), promotes the γ­secretasemediated cleavage of the APP C­terminal fragment after its generation by β­secretase80. A more recent study by the same group suggested that activation of the DOR promotes the translocalization of a complex consisting of the DOR, β­secretase and γ­secretase from the cell surface to the late endosomes and lysosomes (LEL), which results in enhanced β­ and γ­secretase proteolysis of APP78. In a mouse model of AD, administration of natrindole, a selective DOR antagonist, improved spatial learning and reference memory, and reduced the amyloid plaque burden78. Similarly, in vivo knock down of the DOR reduced amyloid­β40 accumulation in the hippoc ampus of an AD mouse model. However, there was no effect on the more hydrophobic (and therefore more toxic) amyloid­β42 (ReF. 78). by contrast, administration of a μ­opioid receptor (MOR) antagonist had no effect on amyloid­β generation or amyloid plaque formation and was unable to reverse the learning and memory deficiency of the AD mouse model78, although another group reported improved spatial memory retention in this transgenic AD mouse model81. DOR binding is decreased in the amygdala and ventral putamen, and MOR binding is decreased in the hippocampus and subiculum79 of post­mortem brain samples from patients with AD. Elevated hippocampal levels of enkephalin, the ligand for these receptors, have been detected in AD transgenic mice and in the human AD brain81,82. Excessive stimulation by enkephalin may uncouple the opioid receptors from G proteins, resulting in receptor internalization83,84 and reduced receptor binding in patients with AD79,85. These adaptive changes in opioid receptor expression in response to increased enkephalin levels might limit the efficacy of opioid receptor antagonists in AD and could explain the variable effects of different DOR antagonists on amyloid­β generation in AD transgenic mouse models.
Regulation of g-secretase The γ-­secretase complex is composed of four integral membrane proteins: the catalytic component presenilin 1 (PS1) or PS2 and the essential cofactors nicastrin, anterior pharynx defective 1 (APH1) and presenilin enhancer 2 (PEn2)86. Proteolysis of the α­ cleavage product C83 by the γ­secretase complex generates a short p3 fragment, which precludes formation of amyloid­β. by contrast, proteolysis of the β­secretase product C99 by the γ­secretase complex generates the amyloid­β peptide, which ranges in length from 35 to 43 residues (FIG. 1). The majority of amyloid­β produced is 40 amino acids in length (amyloid­β40), whereas a small proportion (~10%) is the 42­residue variant (amyloid­β42). Several γ­secretase inhibitors have been developed but they have limited clinical efficacy owing to the severe side effects associated with inhibition of the notch receptor, which is a substrate for γ­secretase proteolysis. Therefore, determination of the cellular mechanisms that specifically regulate amyloid­β generation by γ­secretase is of crucial importance for understanding the factors that cause AD and could highlight new therapeutic targets.

b 2‑adrenergic receptor. Stimulation of β2­AR increases amyloid­β generation in vitro, independently of an elevation in cAMP levels80. In an AD transgenic mouse model, treatment with a β2­AR agonist or antagonist respectively increased and decreased the amyloid plaque burden80. It has been suggested that the β2­AR constitutively associates with PS1 at the plasma membrane and undergoes clathrin­mediated endocytosis together with the γ­secretase complex following agonist stimulation80. This proposed localization of the γ­secretase in LEL compartments, which is supported by other studies87,88, could promote cleavage of C99 and thereby the generation of amyloid­β80. As a therapeutic application, it will be important to determine whether β2­AR activation also modulates cleavage of the notch receptor, given the adverse side effects of targeting γ­secretase discussed above. Importantly, the β2­AR is expressed in the hippocampus and the cortex in humans89, and polymorphisms in the gene encoding the β2­AR are associated with an increased risk of developing sporadic lateonset AD90, providing support for the potential clinical relevance of the in vitro and AD mouse model findings.
G protein‑coupled receptor 3. G protein­coupled receptor 3 (GPR3) is an orphan GPCR with a putative ligand91 that has not been validated92,93. The receptor was identified as a modulator of amyloid­β generation in a high­throughput functional genomics screen designed to identify potential therapeutic targets for AD92. GPR3 is strongly expressed in neurons in the hippocampus, amygdala, cortex, entorhinal cortex and thalamus in the normal human brain94,95, and its expression is increased in a subset of patients with sporadic AD92. Several lines of evidence support the involvement of GPR3 in the generation of amyloid­β. In vitro models of AD suggest that this effect is independent of its ability to stimulate the production of cAMP92. In an AD transgenic mouse model96, hippocampal overexpression of GPR3 enhanced amyloid­β40 and amyloid­β42 generation in the absence of an effect on γ­secretase expression92. Genetic ablation of Gpr3 in these mice dramatically reduced amyloid­β40 and amyloid­β42 levels92, demonstrating that endogenous GPR3 is involved in amyloid­β generation. Further in vitro studies suggested that GPR3 promotes increased association of the individual γ­secretase complex components within detergent­resistant membrane domains and stabilizes the mature γ­secretase complex92. Thus, similar to the β2­AR, the effect of GPR3 signalling on amyloid­β generation is not mediated through an elevation in cAMP levels. Rather, both GPCRs modulate the trafficking and/or localization of the γ­secretase complex to membrane domains where it can more efficiently process the β­secretase product C99. Importantly, the in vitro effect of GPR3 expression on amyloid­β generation occurs in the absence of an effect on notch processing, suggesting that GPR3 can selectively target specific γ­secretase pathways.
CXC‑chemokine receptor 2. The CXC­chemokine receptor type 2 (CXCR2) is abundantly expressed in neurons and is strongly upregulated in a subpopulation of neuritic plaques in the post­mortem human AD brain97,98. In an AD transgenic mouse model, treatment with the CXCR2 antagonist Sb­225002 reduces amyloid­β40 levels99 and is accompanied by a reduction in PS1–C­terminal fragment (CTF) levels, resulting in a probable decrease in the proteolytically active mature γ­secretase complex99. Crossing the Cxcr2­deficient mouse with an AD transgenic mouse also results in a decrease in amyloid­β40 and amyloid­β42 generation, and γ­secretase complex expression100. In vitro evidence suggests that antagonism of CXCR2 reduces expression levels of other γ­secretase complex components, inhibiting generation of both the AICD and the notch intracellular domain. Whether CXCR2 is involved in enhanced turnover, degradation or stabilization of the PS1–CTF has not been determined. However, inhibition of Jun n­terminal kinase (JnK) activity, which is involved in signalling downstream of CXCR2, correlates with reduced phosphorylation and stability of the PS1–CTF101,102. Given that antagonism of CXCR2 leads to general changes in γ­secretase expression and activity, it will be challenging to therapeutically target CXCR2.
GPCRs and amyloid-b toxicity One of the most puzzling aspects of the amyloid cascade hypothesis is why amyloid­β exerts a neurotoxic effect on cells. There is no clear correlation between exposure of the brain to amyloid­β plaques and neurodegeneration and, in cell culture models, the toxicity associated with amyloid­β is variable and poorly understood. Small oligomeric structures of amyloid­β, known as amyloidβ­derived diffusible ligands (ADDLs)103, cause synaptotoxicity, interfering with glutamate signalling at several levels, including direct and indirect effects on Ca2+ levels, endocytosis, and possibly membrane damage and clustering of various membrane proteins. A further complication is that a component of the toxicity associated with amyloid­β might be the consequence of a general mechanism such as interaction with the plasma membrane, which could affect multiple GPCRs. Moreover, several GPCRs are involved in neuro inflammation, with beneficial or detrimental effects on amyloid­β­mediated toxicity depending on the model under investigation. Thus, it remains unclear how the involvement of GPCRs in amyloid­-β ­mediated toxicity can be clinically exploited. Studies on the angiotensin type 2 receptor (AT2R), the adenosine A2A receptor (A2AR) and CC­chemokine receptor 2 (CCR2) provide insight into this complicated matter.

Figure 3 | Amyloid-β toxicity and deregulation of AT2r and M1 mAchr signalling . Oxidative stress and amyloid-β (Aβ) accumulation leads to an increase in reactive oxygen species (ROS) generation and dimerization of angiotensin type 2 receptors (AT2R). An increase in levels of the protein-crosslinking enzyme transglutaminase, as occurs in Alzheimer’s disease, and further Aβ deposition trigger crosslinking and subsequent oligomerization of AT2R dimers. The AT2R oligomers sequester Gαq/11 and thereby inhibit Gαq/11 from coupling to M1 muscarinic acetylcholine receptors (M1 mAChRs). Sequestration of Gαq/11 results in tau phosphorylation, neuronal degeneration and Alzheimer’s disease progression. PKC, protein kinase C. Figure is reproduced, with permission, from REF. 111 © (2009) American Association for the Advancement of Science.

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GPCRs and amyloid-b degradation Promoting amyloid­β clearance from the brain is an alternative therapeutic strategy to inhibition of amyloid­β generation. Such an approach is the basis for the passive and active immunotherapy with amyloid­βspecific antibodies. However, stimulation of GPCRs, in particular the somatostatin receptor, could represent an interesting alternative approach to promoting amyloid­β clearance, as these GPCRs induce expression of amyloidβ­degrading enzymes, such as neprilysin, in the brain. A combination of memory enhancement, neuroprotection and anti­amyloid­β activity makes this an attractive therapeutic approach for AD.
Somatostatin receptors. Somatostatin (also known as somatotropin release­ inhibiting factor, SRIF) is a regulatory peptide with two bioactive forms, SRIF14 and SRIF28, which are widely expressed throughout the CnS and function in neurotransmission, protein secretion and cell proliferation133,134. Expression of the two most abundant SRIF receptors in the brain, somatostatin receptor type 2 (SSTR2) and SSTR4, is reduced in the cortex of human patients with AD135. Interestingly, intracerebroventricular injection of amyloid­β25–35 results in a selective decrease in SSTR2 mRnA and protein levels in the temporal cortex of rats, whereas cognitive deficits correlate with reduced SRIF concentrations in the CSF136 or middle front gyrus (brodmann area 9)137. SRIF levels are also reduced in the CSF136, cortex135 and hippocampus138 of patients with AD. Compelling evidence suggests that SRIF is a modulator of neprilysin activity in the brain139. neprilysin, one of the main amyloid­β­degrading enzymes, regulates the steady state levels of amyloid­β40 and amyloid­β42 in vivo140. SRIF has been shown to significantly elevate neprilysin levels in primary murine cortical neuronal cultures, which accompanies a reduction in amyloid­β42 levels139. Conversely, neprilysin activity and localization are altered in the hippocampus of SRIF­deficient mice, with a corresponding increase in amyloid­β42 levels139. There are conflicting results from AD transgenic mouse models, which show either an increase141 or a decrease in SRIF levels142. Further work is necessary to clarify the cause of the changes in SRIF levels in these AD models.

Figure 4 | Adenosine A2A receptor and amyloid-β-mediated toxicity. a | Amyloid-β (Aβ) deposition has been shown to activate the p38 mitogen-activated protein kinase (MAPK) signalling pathway, which leads to Aβ-induced neurotoxicity. Pharmacological blockade of the adenosine A2A receptor (A2AR) with the compound SCH 58261 reduces Aβ-induced p38 MAPK phosphorylation, synaptotoxicity and cognitive impairment. b | Similarly, caffeine, an A2AR antagonist, is also protective against Aβ-mediated toxicity and may regulate the expression levels of the β-secretase, via the cRaf-1/nuclear factor-κB pathway and presenilin 1, which leads to a decrease in Aβ40 and Aβ42 deposition and is protective against cognitive impairment in an Alzheimer’s disease mouse model. Solid arrows represent direct signalling pathways and dashed arrows represent signalling via intermediates that are not shown. JNK, Jun N-terminal kinase.

Box 2 | GPCRs, diabetes and Alzheimer’s disease Glucagon-like peptide 1 receptor Type 2 diabetes (T2D) has been identified as a risk factor for Alzheimer’s disease (AD)155, and insulin signalling has a role in learning and memory156-158, which potentially links insulin resistance to AD dementia. Indeed, deregulated insulin signalling has been observed in brains of patients with AD and may contribute to the development of AD159. The combination of insulin with other antidiabetic medications is also associated with lower amyloid plaque density and a diminution of the cognitive decline associated with AD160,161. Strategies have therefore been developed to normalize insulin signalling in the brain to deter the progression of AD162. One promising intervention is the use of the incretin hormone glucagon-like peptide 1 (GLP1) as a treatment for neurodegenerative diseases163. In vivo administration of GLP1 or exendin-4, a more stable analogue of GLP1, reduces endogenous levels of amyloid-β40 in the mouse brain and protects against cell death164. In addition, GLP1 and the stable analogue (Val8)GLP1 enhance long-term potentiation (LTP) and reverse the LTP impairment induced by amyloid-β25-35 administration in rodents, which might underlie an improvement in cognitive function165. Most recently, (Val8)GLP1 also prevented amyloid-β40-induced impairment in late-phase LTP, and spatial learning and memory in rodents166. Some evidence also suggests that the desensitization of insulin receptors that occurs in AD can be reversed by activation of GLP1 receptors (GLP1Rs)167. GLP1 binds to GLP1R, which activates diverse signalling pathways, including cyclic AMP, protein kinase A, phospholipase C, phosphatidylinositol 3-kinase, protein kinase C and mitogen-activated protein kinase168–171. GLP1R-deficient mice display an impairment in synaptic plasticity163 and a decrease in the acquisition of contextual learning, a learning deficit that can be reversed following hippocampal gene transfer of Glp1r172. By contrast, overexpression of GLP1R through hippocampal gene transfer markedly enhanced learning and memory in rodents172. Taken together, these studies suggest that the GLP1R represents a novel and promising therapeutic target for AD. Amylin receptor Amylin (also known as islet amyloid polypeptide) is a peptide that was first isolated from amyloid deposits from the pancreatic islets of Langerhans of patients with type 2 diabetes173. Interestingly, human amylin, which acts through the G protein-coupled amylin receptor, possesses amyloidogenic and neurotoxic properties similar to amyloid-β174. Accordingly, treatment of rat neuronal cultures with an amylin receptor antagonist, AC187, attenuates amyloid-β42- and amylin-induced neurotoxicity by blocking caspase activation175. It would be interesting to determine whether treatment with GLP1 could alleviate the cognitive deficits, and to determine the expression levels of GLP1R in this diabetic AD mouse model. Most recently, studies conducted by crossing two T2D mouse models with an AD mouse model have provided further mechanistic insight into the relationship between diabetes and AD, demonstrating that the onset of diabetes exacerbates cognitive dysfuntion in the absence of an elevation in amyloid-β levels and leads to increased cerebrovascular inflammation and amyloid angiopathy176. Conversely, the diabetic AD mice display an accelerated diabetic phenotype relative to the diabetic mouse model alone, suggesting that the amyloid pathology may adversely affect the T2D and vice versa.

Concluding remarks numerous drug discovery efforts target the inhibition of amyloid-­β production, the prevention of amyloid­β aggregation and the enhancement of amyloid-­β clearance. Although these may seem to be straightforward biochemical pathways, several feedback loops enhance not only amyloid­β deposition but also its toxicity, clearance and overall impact on memory function and neuronal health. Such feedback loops also imply that a monotherapy will not be sufficient to prevent the progression of AD. based on the discussion above, it is clear that several GPCRs are involved at many stages of AD disease progression (TABle 1). There also seems to be a pathologically reinforcing loop between type 2 diabetes and AD, with GPCRs providing an avenue for therapeutic intervention for both diseases (BOX 2). Drugs that target GPCRs could diversify the symptomatic therapeutic portfolio for AD and potentially provide disease­modifying treatments. In this sense, they complement the current areas of investigation, which are primarily focused on secretase inhibitors77 and amyloid immunotherapy144. Given that the current anti­amyloidogenic therapy under development is considered to be most effective as a preventative measure or in early stages of AD, additional drugs that preferentially enhance cognition will become a necessary complement to treatment, especially as the disease progresses to more advanced stages. In this regard, GPCRs represent the largest therapeutic target in the pharmaceutical industry and provide ample opportunities for AD­related drug development. nevertheless, progress in the field is hampered by the difficulty in developing highly receptor­specific ligands and the adverse side effects of currently available drugs. Recent advances in the GPCR field suggest that a more functional approach towards the classification of GPCRs, which are now organized according to structural similarity, might enhance the therapeutic potential of GPCRs and assist in the development of selective GPCR candidate drugs for AD and many other diseases.

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