Views on amyloid hypothesis and secretase inhibitors for treating Alzheimer's disease: progress and problems

Alzheimer's disease is a form of sporadic, age-related dementia. According to the "amyloid hypothesis", the processing of beta-amyloid precursor protein (APP) leads to the formation of senile plaque aggregates which subsequently congest normal neurological functions. Currently, prophylaxis is testimonial, while treatment relies mainly on symptomatic relief. This review emphasizes the importance of disrupting the pathological processing of APP via alpha-secretase activators, beta- and gamma-secretase inhibitors, and compounds that bind APP. The style of writing should appeal to those with strong interests in medicinal chemistry with an equal balance of medicine and chemistry.     

Pharmacotherapy for Alzheimer's disease: progress and prospects

The number of people with Alzheimer's disease has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is, therefore, a substantial and increasing need for effective pharmacotherapy. Increased understanding of disease pathophysiology has led to palliative treatments for both cognitive and non-cognitive changes in behaviour. This, together with the prospect of drugs that slow or perhaps even halt the course of the disease, raises hope that this devastating disorder will soon be more amenable to pharmacotherapy with new drugs that either ameliorate specific symptoms or alter the course of the disease.     

Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: novel PET/SPECT imaging probes for diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease of the brain associated with irreversible cognitive decline, memory impairment, and behavioral changes. Postmortem brains of AD patients reveal neuropathologic features, in particular the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), which contain β-amyloid peptides and highly phosphorylated tau proteins. Currently, AD can only be definitively confirmed by postmortem histopathologic examination of SPs and NFTs in the brain. Therefore, SPs and NFTs in the brain may be useful as biomarkers for the differential diagnosis of AD; the detection of individual SPs and NFTs in vivo by positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) should improve diagnosis and also accelerate discovery of effective therapeutic agents for AD. Many PET/SPECT imaging probes for SPs have already been developed. Several of the PET probes have been shown in clinical trials to be useful for the imaging of β-amyloid plaques in living brain tissue. More recently, the development of PET/SPECT probes for in vivo imaging of NFTs is an active area of study in the field of molecular imaging because the appearance of NFT pathology correlates well with clinical severity of dementia. We will review current research on the development of PET/SPECT imaging probes for in vivo detection of SPs and NFTs and their application to diagnosis and therapy of AD.     

Alzheimer's disease and the amyloid cascade hypothesis: ten years on.

The amyloid beta peptide as the major culprit of Alzheimer's disease pathogenesis entered the research arena about a decade ago. The amyloid cascade hypothesis was vividly discussed, supported and contested. Has it held up to all challenges until today? It is alive as ever. The recent identification of the key enzyme involved in amyloid beta generation offered a new target for drug discovery and a novel therapy approach using immunization has successfully eliminated plaque burden in a transgenic mouse. Neurofibrillary tangles, the other hallmark of the disease, were induced in an animal model by amyloid beta peptide.     

Cholinergic therapies for Alzheimer's disease: progress and prospects

Cholinomimetic drugs are now available to treat the cognitive impairments associated with Alzheimer's disease (AD), although evidence indicates that the effects of acetylcholinesterase (AChE) inhibitors on measures of cognitive function may be secondary to an action on attentional mechanisms. There is also convincing evidence suggesting that cholinomimetic drugs (e.g., AChE inhibitors and agents acting on cholinergic receptors) will have utility in the treatment of other, non-cognitive changes in behavior that are often associated with AD. This review describes some of the approaches to cholinergic therapy and considers the symptoms that are best suited to these treatment modalities.     

Neuroprotective therapeutics for Alzheimer's disease: progress and prospects

The number of people with Alzheimer's disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease. In this article I review the neurobiological basis of AD, current progress towards neuroprotective therapeutics, and prospects for the future.     

Synthesis and receptor binding properties of fluoro- and iodo-substituted high affinity sigma receptor ligands: identification of potential PET and SPECT sigma receptor imaging agents.

Unlabeled fluoro- and iodo-substituted ligands exhibiting very high affinity and selectivity for sigma receptors were synthesized based on three different structural classes of sigma receptor ligands. These compounds were evaluated for sigma receptor affinity and specificity in order to assess their potential as PET/SPECT imaging agents. Thus, (+)- and (-)-N-(5-fluoro-1-pentyl)normetazocines [(+)- and (-)-4] based on the (+)-benzomorphan class of sigma ligands were synthesized via N-alkylation of optically pure (+)- and (-)-normetazocine with 5-[(methylsulfonyl)oxy]-1-pentyl fluoride (11). (+)- and (-)-4 displaced [3H](+)-3-PPP with Ki values of 0.29 and 73.6 nM and [3H](+)-pentazocine with Ki values of 10.5 and 38.9 nM, respectively. The second class of PET/SPECT ligands was based upon the N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine class of sigma ligands; N-[2-(3,4-dichlorophenyl)-1-ethyl]-N-(3-fluoro-1-propyl)-2-(1- pyrrolidinyl)ethylamine (5) was obtained via N-alkylation of N-[2-(3,4-dichlorophenyl)-1-ethyl]-2-(1-pyrrolidinyl)ethylamine (14) with 3-fluoropropyl p-toluenesulfonate. 5 exhibited Ki values of 4.22 and 5.07 nM for displacement of [3H](+)-3-PPP and [3H](+)-pentazocine, respectively, comparable with the parent N-propyl compound. Attempts to synthesize N-[2-(3,4-dichlorophenyl)-1-ethyl]-N-[3- [(methylsulfonyl)oxy]-1-propyl]-2-(1-pyrrolidinyl)ethylamine (26), a precursor to 5 that could conceivably be converted to [18F]-5 by treatment with 18F-, proved unsuccessful. The sequence of regioselective nitration, catalytic hydrogenation, and diazotization followed by NaI quench of N-[2-(3,4-dichlorophenyl)-1-ethyl]-N-methyl-2-(1- pyrrolidinyl)ethylamine (2) afforded the iodinated ethylenediamine N-[2-(2-iodo-4,5-dichlorophenyl)-1-ethyl]-N-methyl-2-(1- pyrrolidinyl)ethylamine (8), a potential SPECT ligand for sigma receptors. This compound showed an affinity of 0.54 nM ([3H](+)-3-PPP) comparable with the parent compound 2 (Ki = 0.34 nM, [3H](+)-3-PPP). Ligand 8 exhibited a similar potency against [3H](+)-pentazocine. The third class of high-affinity sigma receptor ligands was rationalized based on rearrangement of the bonds in ethylenediamine 2 to give 1-[2-(3,4-dichlorophenyl)-1-ethyl]-4-(1-propyl)piperazine (3). This compound exhibited very high affinity (Ki = 0.31 nM, [3H](+)-3-PPP) and selectivity for sigma receptors.(ABSTRACT TRUNCATED AT 400 WORDS)     

Low dose oral haloperidol and blood levels in Alzheimer's disease: a preliminary study.

Nineteen patients with probable Alzheimer's disease who manifested psychosis or behavioral disturbance received 0.5 to 5 mg per day of oral haloperidol, with blood levels drawn on a stable daily dose. Oral dose correlated strongly with haloperidol blood levels assessed by radioimmunoassay (r = 0.82, p = .0001). The stronger correlation observed between oral dose and blood level compared with most studies in schizophrenia may be related to the fact that virtually all the Alzheimer's patients were neuroleptic naive, without the alterations in absorption and metabolism known to occur in schizophrenics receiving long-term neuroleptic treatment. Compared with oral dose, blood levels showed stronger relations to changes in symptoms and to changes in severity of extrapyramidal side effects. These preliminary data suggest that the utility of monitoring haloperidol blood levels in patients with Alzheimer's disease merits further investigation.     

Genetics of late-onset Alzheimer's disease: progress and prospect

Genetic susceptibility factors for late-onset Alzheimer's disease remain largely elusive, with the exception of apolipoprotein E4 (APOE e4) as the only confirmed genetic risk factor. Numerous other putative risk markers have been proposed, although all suffer inconsistent replication. These results suggest that modest effect sizes are likely to be the norm for non-APOE-related factors. This unsettling situation has been similar to other complex diseases such as diabetes and cardiovascular diseases until very recently, when a spate of new, although weak, genetic markers has been convincingly linked to these conditions. If we assume that multiple weak factors, together with APOE e4, account for the genetic contribution to late-onset Alzheimer's disease risk, it will require the concerted efforts of the greater Alzheimer's genetics community to pool existing genetic resources and/or data to identify novel genetic risk factors that are genuine. Increased confidence in the disease-associated factors will provide the foundation to develop better diagnostic and prognostic tests, select new drug targets and, perhaps, elucidate pharmacogenetic markers that assist in making the best treatment decisions.     

Florbetapir (18F), a PET imaging agent that binds to amyloid plaques for the potential detection of Alzheimer's disease

Florbetapir (18F), being developed by Avid Radiopharmaceuticals, is an 18F-labeled PET tracer binding to amyloid-β (Aβ) plaques for the potential detection of Alzheimer's disease (AD). Preclinical studies indicated high binding affinity of florbetapir (18F) to Aβ fibrils and specific labeling of Aβ plaques in the cortical regions and hippocampus. In phase I and II clinical trials, florbetapir (18F) clearly differentiated patients with AD from healthy controls and uptake was most prominent in the precuneus. The neocortical-to-cerebellar tracer uptake ratio reached a plateau within 50 min post-injection and high-quality images were acquired with 5 to 10 min image acquisition time with 370 MBq of florbetapir (18F). Results from an ongoing phase III clinical trial confirmed a strong correlation between florbetapir (18F) PET images and postmortem assessment of Aβ deposition. No serious adverse events were reported in any of the clinical trials of florbetapir (18F). At the time of publication, a marketing application for florbetapir (18F) had been submitted to the US FDA. The fast kinetics and strong evidences of radiological-pathological correlation are advantages of florbetapir (18F) over other 18F-labeled amyloid PET tracers. This tracer has a potential to serve as an agent for preclinical detection of AD-related pathology in the large elderly population.     

Muscarinic agonists for the treatment of Alzheimer's disease: progress and perspectives

Much interest has focused on the development of selective muscarinic agonists for the treatment of Alzheimer's disease (AD). Cholinergic replacement therapy is thought to be beneficial in alleviating some of the cognitive dysfunctions in this disorder. The cholinergic neuronal tracts are involved in memory and learning processes, and the extent of the degeneration of the cortical projections correlates with the severity of the dementia. An M1 selective muscarinic agonist may be effective in treating at least some of the cognitive symptoms in AD. Highly selective M1 agonists, producing cellular excitation, should be beneficial in AD, regardless of the extent of degeneration of presynaptic cholinergic projections to the frontal cortex or hippocampus. Functional abnormalities in AD may also occur along various signal transduction pathways mediated, in part, at least, by muscarinic receptors. In general, activities associated with mAChR subtypes and m1 receptors, in particular, indicate that M1 agonists may also be useful for this aspect of AD. Mismetabolism of amyloid precursor proteins (APPs) may induce AD. Recent studies indicate that the formation of the b-amyloid peptide (Abeta) and amyloid plaques is linked to the loss of cholinergic function in AD. New data on the activation of m1 mAChRs in conjunction with recent findings that the induction of such receptors stimulates neurotrophic-like activities, decreases tau phosphorylation and inhibits apoptosis indicate that restoring the cholinergic tone in AD may be useful both in improving memory function and in altering the onset and progression of AD dementia. This article focuses on the recent, promising developments in this field and assesses the value of muscarinic agonists currently under development for the treatment of AD.     

The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics

The amyloid cascade hypothesis, which posits that the deposition of the amyloid-β peptide in the brain is a central event in Alzheimer's disease pathology, has dominated research for the past twenty years. Several therapeutics that were purported to reduce amyloid-β production or aggregation have failed in Phase III clinical testing, and many others are in various stages of development. Therefore, it is timely to review the science underpinning the amyloid cascade hypothesis, consider what type of clinical trials will constitute a valid test of this hypothesis and explore whether amyloid-β-directed therapeutics will provide the medicines that are urgently needed by society for treating this devastating disease.     

Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease.

Four novel analogues (8-11) of cymserine (2) were synthesized by methods similar to those recently developed for the total syntheses of N8-norphenserine (Yu, Q. S.; et al. J. Med. Chem. 1997, 40, 2895-2901) and N1,N8-bisnorphenserine (Yu, Q. S.; et al. J. Med. Chem. 1998, 41, 2371-2379). As our structure-activity studies predicted, these compounds are highly potent and selective inhibitors of human butyrylcholinesterase (BChE) and will test the novel hypothesis that BChE inhibitors are useful in the treatment of Alzheimer's disease. In a similar manner, the same modifications that provided BChE selectivity were applied to the acetylcholinesterase (AChE)-selective inhibitor, tolserine (5), to provide the novel tolserine analogues 12-15. As predicted, these modifications altered the AChE-selective action of tolserine (5) to favor a lack of cholinesterase enzyme subtype selectivity.     

Brain clearance of Alzheimer's amyloid-beta40 in the squirrel monkey: a SPECT study in a primate model of cerebral amyloid angiopathy

Squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Previous studies suggested that circulating amyloid-beta40 peptide (Abeta40) crosses the blood-brain barrier (BBB) and may therefore enhance cerebrovascular amyloidosis in aged squirrel monkeys. In the present study, we used single photon emission computed tomography (SPECT) to determine elimination of 123I-Abeta40 and 99mTc-DTPA, an extracellular marker, from the brain in squirrel monkeys at different age. Following intracerebral microinfusions, the time-activity brain clearance curves indicated bi-exponential removal of 123I-Abeta40 with an initial rapid washout (1.1 < or = t 1/2 < or = 2.7 h). This, plus the observed appearance of 123I-radioactivity in plasma suggest significant brain-to-blood transport. In contrast, 99mTc-DTPA was removed slowly by brain interstitial fluid bulk flow (monoexponential decay with 6.8 < or = t 1/2 < or = 16.8 h). A comparison of three middle aged (11-16 years old) vs. two old (22 yrs old) monkeys was consistent with an age-related decline in the BBB capacity to remove 123I-Abeta from the brain. This correlated with an age-dependent increase in A1beta40/42 cerebrovascular immunoreactivity and amyloid deposition. Thus, vascular clearance plays an important role in reducing Abeta levels in the squirrel monkey brain and impaired Abeta40 elimination across the BBB may contribute to the development of CAA.     

Characteristics of plasma protein binding of tacrine hydrochloride: a new drug for Alzheimer's disease

The aim of this study was to characterise the plasma protein binding of tacrine hydrochloride (THA) in vitro. Binding was assessed in the plasma of 11 healthy individuals aged 20 to 27 years using ultrafiltration followed by HPLC assay.At THA concentrations from 10 to 100 ng/ml protein binding ranged from 78.6 to 71.0%. Binding to commercially available human albumin ranged from 41.7 to 38.3% and to human ₁-acid glycoprotein from 23.1 to 12.4% over the THA concentrations from 25 to 100 ng/ml.THA binding and total plasma protein, plasma albumin and ₁-acid glycoprotein were measured in healthy young subjects (n=13), healthy elderly individuals (n=12) and patients hospitalised with acute illnesses (n=8). There were significant differences between the groups in total plasma protein, plasma albumin and in ₁-acid glycoprotein but no differences in the protein binding of THA which remained constant at about 75%. There was no correlation between THA binding and any plasma protein concentration.The THA binding was not high enough to be of major significance clinically or to reduce the validity of total plasma THA measurement in therapeutic monitoring.     

Antioxidants as a potential therapy against age-related neurodegenerative diseases: amyloid Beta toxicity and Alzheimer's disease

Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder with distinct neuropathological features. Extracellular plaques, consisting of aggregated amyloid peptides of 39-43 amino acids are one of the most prominent pathological hallmarks of this disease. Although the exact neurochemical effector mechanism of Abeta aggregation is not yet elucidated, age-associated disturbances of metal ion metabolism have been proposed to promote the formation of aggregates from soluble Abeta. Oxidative stress is postulated to be a downstream effect of Abeta-metal ion interactions. Therefore, the modulation of brain metal metabolism and attenuation of oxidative stress by antioxidant molecules are proposed as a potential therapeutic intervention in AD. Here, we summarize the recent literature focused on APP/Abeta-metal ion interactions and the use of antioxidant metal chelators as potential therapy against AD.     

Processing of amyloid precursor protein as a biochemical link between atherosclerosis and Alzheimer's disease

Macrophage activation in atherosclerotic plaques plays a role in plaque destabilization, rupture and subsequent atherothrombosis. Platelet phagocytosis that occurs within human atherosclerotic plaques can activate macrophages and it has been suggested that the platelet constituent amyloid precursor protein (APP) is involved. Recent studies show that amyloid beta (Abeta), a peptide extensively studied in Alzheimer's disease and that is cleaved from APP by beta- and gamma-secretase, and/or Abeta-like peptides are also present in human atherosclerotic plaques, in particular in activated, inducible nitric oxide synthase (iNOS) expressing perivascular macrophages that had phagocytized platelets. In vitro studies confirm that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to Abeta-like peptides, resulting in iNOS induction. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and HMG-CoA reductase inhibitors (statins), two classes of drugs reported to affect APP processing and Abeta formation in Alzheimer's disease, have been evaluated for their capacity to inhibit macrophage activation evoked by platelet phagocytosis. Remarkably, the same NSAIDs reported to alter gamma-secretase activity in Alzheimer's disease also reduce macrophage activation after platelet phagocytosis and inhibit formation of Abeta-containing peptides. From the statins investigated (fluvastatin, atorvastatin, simvastatin, pravastatin, lovastatin and rosuvastatin) only fluvastatin and atorvastatin selectively inhibit macrophage activation after platelet phagocytosis, possibly through inhibition of Rho activity. Taken together, these new findings point to the involvement of platelet-derived APP in macrophage activation in atherosclerosis and suggest a biochemical link between atherosclerosis and Alzheimer's disease. Accordingly, drugs interfering with APP processing might have an impact on both diseases.     

Improved brain delivery of a nonsteroidal anti-inflammatory drug with a synthetic glyceride ester: a preliminary attempt at a CNS drug delivery system for the therapy of Alzheimer's disease

1,3-Diacetyl-2-ketoprofen glyceride (DAKG), a prodrug of ketoprofen, was synthesized as a model compound in our attempt to develop a central nervous system (CNS) drug delivery system to treat Alzheimer's disease. The primary purpose of the present study is to test whether DAKG improves the delivery of ketoprofen to the brain and to quantitatively evaluate several factors that influence the brain distribution of this prodrug. ddY mice were injected with either ketoprofen or DAKG at a dose of 40 micromol/kg and then the plasma and brain pharmacokinetics of these agents were assessed. The brain uptake clearance of ketoprofen and DAKG across the BBB was measured by in situ mouse brain perfusion. In addition, the efflux permeability of ketoprofen through the BBB was evaluated using the in vivo mouse brain microdialysis technique. The in vivo metabolism of DAKG in the brain was assessed by a short infusion into the internal carotid artery coupled with the brain metabolism index (BMI) method. Administration of DAKG produced an approximately 3-fold increase in the area under the brain concentration - time curve of ketoprofen, compared with administration of ketoprofen itself. The brain uptake clearance (CL(in) ) of ketoprofen across the BBB was 0.0308 +/- 0.0046 mL/min/g whereas the CL(in) of DAKG was 1.60 +/- 0.16 mL/min/g, suggesting a marked increase in BBB permeability following lipidization of ketoprofen. The BMI method confirmed that DAKG is taken up by the brain to rapidly release ketoprofen in a dose-dependent manner. The in vitro metabolism studies revealed that isolated bovine brain capillaries as well as whole brain homogenate have the hydrolysis activity to DAKG. In addition, the brain concentration of ketoprofen after DAKG administration was maintained for a significant period following co-administration of probenecid. These results suggest that DAKG improves the delivery of ketoprofen to the brain, and this improved delivery is due to avid uptake of DAKG across the BBB followed by rapid hydrolysis to ketoprofen within the brain. The ketoprofen produced in the brain was probably cleared by the active efflux system operating in the BBB. Significant inhibition of this efflux system by co-administration of probenecid could result in a sustained concentration of ketoprofen in the brain following DAKG administration.