Biomedical subjects

D K Lahiri

Publications and source records attributed to D K Lahiri.

At least 19 recordsLinked to original sources

PubMed2005

Thyrotropin-releasing hormone (protirelin) inhibits potassium-stimulated glutamate and aspartate release from hippocampal slices in vitro.

Excess excitatory amino acid release is involved in pathways associated with seizures and neurodegeneration. Thyrotropin-releasing hormone (TRH; protirelin), a brain-derived tripeptide, has shown efficacy in the treatment of such disorders, yet its mechanism of neuroprotection is poorly understood. Using superfused hippocampal slices, we tested the hypothesis that TRH could inhibit evoked glutamate/aspartate release in vitro. Rat hippocampal slices were first equilibrated in oxygenated Krebs buffer (KRB) (120 min) then superfused for 10 min with KRB (control), or KRB containing 0.1, 1, or 10 microM TRH respectively, prior to and during 5 min depolarization with high potassium KRB (50 mM [K(+)] +/- TRH). Fractions (1 min) were collected during the 5 min stimulation and for an additional 10 min thereafter and analyzed for glutamate and aspartate by HPLC. TRH had no effect on baseline glutamate/aspartate release, while all three TRH doses significantly (P < 0.05) inhibited peak 50 mM [K(+)]-stimulated glutamate/aspartate release, and glutamate remained below control (P < 0.05) at 15 min post stimulation. A 5 min pulse of TRH (10 microM) had no affect on basal glutamate/aspartate release, whereas the TRH pre-pulsed slices failed to release glutamate/aspartate by [K(+)]-stimulation given 15 min later. These results are the first to show a potent and prolonged inhibitory effect of TRH on evoked glutamate/aspartate release in vitro. These initial studies suggest that exogenous and/or endogenous TRH may function, in part, to modulate excess glutamate release in specific CNS loci. Additional studies are in progress to fully understand the mechanism of this potent effect of TRH and its implication in various CNS disorders.

Animals↗

PubMed2004

Cholesterol and APOE genotype interact to influence Alzheimer disease progression.

In this retrospective analysis of 443 Alzheimer disease (AD) patients from a 30-week tacrine trial, change in Alzheimer's Disease Assessment Scale score from baseline to final value was significantly associated with a total serum cholesterol/APOE genotype interaction. Disease progression in the no-APOE epsilon4 allele/high-cholesterol subgroup was greater than in the normal-cholesterol subgroups with or without epsilon4. Cholesterol levels and APOE genotype may interact to affect AD progression. The results are consistent with preclinical data on cholesterol's effects in AD.

Aged↗

PubMed2004

Chronic exposure to aluminum in drinking water increases inflammatory parameters selectively in the brain.

A link between aluminum (Al) exposure and age-related neurological disorders has long been proposed. Although the exact mechanism by which the metal may influence disease processes is unknown, there is evidence that exposure to Al causes an increase in both oxidative stress and inflammatory events. These processes have also been suggested to play a role in Alzheimer's disease (AD), and exposure to the metal may contribute to the disorder by potentiating these events. Al lactate (0.01, 0.1, and 1 mM) in drinking water for 10 weeks increased inflammatory processes in the brains of mice. The lowest of these levels is in the range found to increase the prevalence of AD in regions where the concentrations of the metal are elevated in residential drinking water (Flaten [2001] Brain Res. Bull. 55:187-196). Nuclear factor-kappaB as well as tumor necrosis factor-alpha (TNF-alpha) and interleukin 1alpha (IL-1alpha) levels were increased in the brains of treated animals. The mRNA for TNF-alpha was also up-regulated following treatment. Enhancement of glial fibrillary acidic protein levels and reactive microglia was seen in the striatum of Al-treated animals. The level of amyloid beta (Abeta40) was not significantly altered in the brains of exposed animals. Insofar as no parallel changes were observed in the serum or liver of treated animals, the proinflammatory effects of the metal may be selective to the brain. Al exposure may not be sufficient to cause abnormal production of the principal component of senile plaques directly but does exacerbate underlying events associated with brain aging and thus could contribute to progression of neurodegeneration.

Aluminum Compounds↗

PubMed2004

Lack of N1L gene expression results in a significant decrease of vaccinia virus replication in mouse brain.

Vaccinia virus encodes secretory proteins termed virokines. One of the major virokines encoded by the N1L open reading frame is the 13.8 kDa protein. A recombinant virus, termed vGK5, lacking this protein when injected intracranially into mice, has one of the highest levels of in vivo attenuation achieved by deletion of any single open reading frame of vaccinia virus. Here we show that the 13.8 kDa protein significantly enhances viral replication within brain tissue; however, analysis of histology, neutrophil infiltrate, and nitric oxide synthase activity of brain tissue shows no significant differences between wild-type vaccinia virus and vGK5. Since there is poor growth of vGK5 virus in the brain, the possibility of postvaccinial encephalitis is significantly diminished. Mice injected with vGK5 became resistant to the lethal effects of vaccinia virus, indicating that vGK5 is immunogenic in the brain without being virulent and therefore is a vaccine candidate. This suggests that should vGK5 reach the brain it will not replicate efficiently but still serve as a live vaccine.

Amino Acid Sequence↗

PubMed2004

Retardation of brain aging by chronic treatment with melatonin.

Slowing the functional decline in the aging brain is not only relevant to nonpathological senescence but also to a broad range of neurodegenerative diseases. Although disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are not found in the young adult, they gradually manifest with increasing age. AD, in particular, is an increasing major public health concern as the population ages; therapies that delay disease onset will markedly reduce overall disease prevalence. Aging of the brain has been repeatedly associated with cumulative oxidative damage to macromolecules and to abnormal levels of inflammatory activity. Melatonin has attained increasing prominence as a candidate for ameliorating these changes occurring during senescence. Recent research has focused on supplementation with dietary melatonin designed to elucidate the specific key intracellular targets of age-related inflammatory events, and the optimal means of affording protection of these targets. This report summarizes the progress made in this area.

Aging↗

PubMed2004

Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents.

Alzheimer's disease (AD) is characterized by progressive dementia caused by the loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning and brain deposits of amyloid beta peptide (A beta) and neurofibrillary tangles (NFT). A small fraction of early onset familial AD (FAD) is caused by mutations in genes, such as the beta-amyloid precursor protein (APP) and presenilins that increase the load of A beta in the brain. These studies together with findings that A beta is neurotoxic in vitro, provide evidence that some aggregates of this peptide are the key to the pathogenesis of AD. The yield of A beta and the processing and turnover of APP are regulated by a number of pathways including apolipoprotein E, cholesterol and cholinergic agonists. Early studies showed that muscarinic agonists increased APP processing within the A beta sequence (sAPP alpha). More recently, we have presented evidence showing that some, but not all, anticholinesterases reduce secretion of sAPP alpha as well as A beta into the media suggesting that cholinergic agonists modulate A beta levels by multiple mechanisms. Herein we review the recent advances in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. We propose and support the position that the influence of cholinergic stimulation on amyloid formation is critical in light of the early targeting of the cholinergic basal forebrain in AD and the possibility that maintenance of this cholinergic tone might slow amyloid deposition. In this context, the dual action of certain cholinesterase inhibitors on their ability to increase acetylcholine levels and decrease amyloid burden assumes significance as it may identify a single drug to both arrest the progression of the disease as well as treat its symptoms. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. We critically discuss recent trends in AD research, from molecular and genetic to clinical areas, as it relates to the effects of cholinergic agents and their secondary effects on A beta. Finally, we examine different neurobiological mechanisms that provide the basis of new targets for AD drug development.

Alzheimer Disease↗

PubMed2003

Vaccinia virus complement control protein modulates inflammation following spinal cord injury.

The vaccinia virus complement control protein (VCP) possesses multiple modulatory functions. Functioning as a complement inhibitory protein, VCP reduces production of proinflammatory chemotactic factors produced during complement activation. Additionally, VCP binds heparin and heparan sulfate proteoglycans, resulting in added functions shown to block monocyte chemotaxis in vitro. Using an in vivo spinal cord contusive injury model in rats, the inflammation-modulating abilities of VCP were evaluated. The results of both myeloperoxidase assaying and H&E stained section counts of spinal tissue reveal that neutrophil infiltration to the area of the lesion was reduced in animals that received VCP as compared to saline-injected controls.

Animals↗

PubMed2003

Does nitric oxide synthase contribute to the pathogenesis of Alzheimer's disease?: effects of beta-amyloid deposition on NOS in transgenic mouse brain with AD pathology.

Oxidative stress is a risk factor for Alzheimer's disease (AD) whose major hallmark includes brain depositions of the amyloid beta peptide (Abeta) derived from the beta-amyloid precursor protein (APP). Our aim was to determine whether or not excessive Abeta deposition would alter nitric oxide synthase (NOS) activity, and thereby affect NOS-mediated superoxide formation. We compared NOS activity in brain extracts between Tg mice (expressing APP Swedish double mutation plus presenilin [PS-1] and nontransgenic [nTg] mice. Five brain regions, including cerebral cortex, hippocampus, cerebellum, and striatum from both nTg and Tg mice showed a detectable level of neuronal (n) NOS activity. Cerebellar extracts from both nTg and Tg mice displayed the highest level of nNOS activity, which was fourfold higher than cortical extracts. Although there was an increase in nNOS activity in Tg brain extracts, this did not attain statistical significance. A similar result was obtained for inducible NOS levels. Our results suggest that excess levels of Abeta failed to both trigger NOS activity and change NOS levels.

Alzheimer Disease↗

PubMed2003

A proximal gene promoter region for the beta-amyloid precursor protein provides a link between development, apoptosis, and Alzheimer's disease.

Abnormalities in regulation of the beta-amyloid precursor protein (APP) gene might be a crucial factor in Alzheimer's disease (AD). Our aim is to study the role of a specific proximal APP promoter element under the apoptotic condition. Our transfection studies with APP promoter deletion constructs indicate that each cell type differently regulates promoter activity. The minimum region that was sufficient to drive basal promoter activity in neuronal PC12 and neuroblastoma SK-N-SH cells was -75/+104 and -47/+104 bp, respectively. In SK-N-SH cells, the -47/+104 construct displayed the highest promoter activity, and the -75/-46 region acted as a negative regulatory element. Results from the gel electrophoretic mobility shift assay (EMSA) indicate that the -75/-46 region binds to a distinct DNA-protein complex with nuclear protein(s) from HeLa, PC12, NIH-3T3, and neuroblastoma cells. EMSA results from HeLa cells, which were stimulated by serum starvation (SR), indicate a significant induction in the signal of the DNA-protein complex from controls. EMSA results from PC12 cells, which were subjected to hypoxia, indicate a significant reduction in the signal. Our results suggest that the -75/-46 region binds to a protein that is upregulated in serum starvation, and downregulated in hypoxia. Because serum starvation contributes to the induction of apoptosis, these results suggest a role of the 30-bp proximal APP promoter element in enhanced apoptotic neuronal cell death.

3T3 Cells↗

PubMed2003

Proteolytic activation of proapoptotic kinase PKCdelta is regulated by overexpression of Bcl-2: implications for oxidative stress and environmental factors in Parkinson's disease.

We previously demonstrated that the organochlorine pesticide dieldrin, a potential chemical risk factor for development of Parkinson's disease (PD), impairs mitochondrial function and promotes apoptosis in dopaminergic PC12 cells. We further demonstrated that caspase-3-dependent proteolytic activation of a member of the novel PKC family, protein kinase Cdelta (PKCdelta), contributes to apoptotic cell death in dopaminergic cells. In the present study, we report that the proapoptotic function of PKCdelta can be regulated by overexpression of the mitochondrial anti-apoptotic protein Bcl2 in dieldrin-treated dopaminergic cells. Exposure to dieldrin (30 or 100 micro M) for 3 h produced a dose-dependent increase in caspase-3 activation and DNA fragmentation in vector-transfected PC12 cells. Overexpression of human Bcl-2 in PC12 cells completely suppressed dieldrin-induced caspase-3 activation and DNA fragmentation. Furthermore, dieldrin-induced proteolytic activation of PKCdelta was also remarkably reduced in Bcl-2-overexpressed cells. Together, these results suggest that the proapoptotic function of PKCdelta can be regulated by mitochondrial redox modulators during neurodegenerative processes.

Animals↗

PubMed2003

Role of cytokines in the gene expression of amyloid beta-protein precursor: identification of a 5'-UTR-binding nuclear factor and its implications in Alzheimer's disease.

One of the major neuropathological characteristics of Alzheimer's disease (AD) is the brain depositions of senile plaques that are mainly composed of toxic amyloid beta-peptide (Abeta), which is generated from a family of Abeta containing precursor proteins (AbetaPP; 695-770 amino acids). The role of cytokines and growth factors has been implicated in the pathogenesis of AD. Our goal is to determine the mode of action of cytokines on the regulation of betaPP gene expression. Here we studied the effect of different cytokines on the activity of 5'-untranslated region (5'-UTR) of betaPP mRNA in human astrocytic cells (U-373). We compared betaPP-5'-UTR activity in the presence of interleukin-1 (IL-1alpha and IL-1beta), transforming growth factor (TGF-beta1) and tumor necrosis factor TNF-alpha1. The astrocytic cells, which were treated separately with these agents, were transfected with either the vector (pSV2CAT) or pSV2UTR-CAT construct containing 90 bp of AbetaPP 5'-UTR +54 to 144 bp). This region was cloned upstream of a reporter chloramphenicol acetyl transferase gene (CAT). Our results indicate that the treatment of pSV2UTR-CAT-transfected cells with either IL-1alpha, IL-1beta, TGF-beta1 or TNF-alpha1 stimulated reporter gene activity in a factor-specific manner. This was consistent with their effects on elevating AbetaPP protein levels. Transfection of the same cells with the pSV2CAT vector lacking 5'-UTR resulted in a reduced reporter gene activity with all treatments studied. DNA-gel shift experiments indicate that the 54/144 region binds to a nuclear protein(s) in a cell type specific manner. These results suggest that 5'-UTR of the AbetaPP gene can respond to the stimulation of different cytokines, which likely regulate AbetaPP transcription and translation via regulatory elements present in the AbetaPP promoter and in 5'-UTR, respectively. The characterization of AbetaPP regulatory elements, including the 5'-UTR, will accelerate the development of novel agents against new targets for AD.

5' Untranslated Regions↗

PubMed2002

Developmental expression of the beta-amyloid precursor protein and heat-shock protein 70 in the cerebral hemisphere region of the rat brain.

Alzheimer's disease (AD) is characterized by depositions of the amyloid beta protein (A beta) in the brain in the form of extracellular plaques and cerebrovascular amyloid. A beta (approximately 4 kDa) is derived from a family of large (approximately 110 kDa) beta-amyloid precursor proteins (APP), which are integral membrane glycoproteins. Although a connection between AD and alcoholism has recently been suggested, this relationship has not been explored at the molecular level. Our hypothesis is that APP has a role in brain development and that abnormal APP levels may be involved in dementia associated with AD and alcoholism. We compared the profile of total APP levels between ethanol naïve alcohol-preferring (P) and alcohol-nonpreferring (NP) rats. We also investigated the possibility that APP levels can be regulated in an age-dependent manner in young rats. We studied the distribution of two proteins in the cerebral hemisphere region of the rat brain at various developmental periods. Six groups composed of the following different ages of rats were used: 7, 14, 21, 36, 43, and 78 (postnatal) days. Cell extracts from different regions of the brain were subjected to Western immunoblotting using mAb22C11. Our results suggest that levels of high-molecular-weight APP bands were greater in brain extracts from 7-day-old P rats than in other samples tested, and that the distribution of APP levels was more uneven in brain extracts from different ages of P than from NP rats. These initial results suggest that APP may play an important role in the early development of the rat brain and the alcohol-preferring trait may influence APP processing in the developing brain.

Alcohol Drinking↗

PubMed2002

Nicotine reduces the secretion of Alzheimer's beta-amyloid precursor protein containing beta-amyloid peptide in the rat without altering synaptic proteins.

Alzheimer's disease (AD) is characterized by cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). Altered metabolism of beta APP, resulting in increased A beta production, appears central in the neuropathology of AD. The processing of the holoprotein beta APP by different "secretase" enzymes results in three major carboxyl-truncated species. One species, which results from the cleavage of beta APP by gamma-secretase, is secreted into the cerebrospinal fluid (CSF) and is called sAPP gamma as it contains an intact A beta domain. Moreover, AD is characterized by cholinergic dysfunction and the loss of synaptic proteins. Reports of an inverse relation between nicotine intake, due to cigarette smoking, and the incidence of AD prompted us to investigate the effects of nicotine on beta APP processing and synaptic proteins in rats and in cell culture. Nicotine, 1 and 8 mg/kg/day, doses commensurate with cigarette smoking, and a higher but well tolerated dose, respectively, was administered over 14 days to rats. Levels of sAPP in the CSF sample were evaluated by Western blot analysis. The higher dose significantly increased levels of total sAPP; however, both doses significantly reduced sAPP gamma, which contains the amyloidogenic portion of A beta. These actions were blocked by nicotinic receptor antagonism. Nicotinic antagonists alone had no effect on either total sAPP or sAPP gamma levels in CSF. Nicotine did not significantly change the intracellular levels of total beta APP in rat brain extracts, which is consistent with neuronal cell culture data. Similarly, levels of vesicular protein, such as synaptophysin, and presynaptic terminal protein SNAP-25 were unaffected by nicotine treatment both in vivo and in cell culture experiments. Taken together, these results suggest that nicotine modifies beta APP processing away from the formation of potentially amyloidogenic products, without altering the levels of synaptic proteins, and that this can potentially offer therapeutic potential for Alzheimer's disease.

Amyloid beta-Protein Precursor↗

PubMed2002

The role of the carboxyl-terminal fragments of amyloid precursor protein in Alzheimer's disease.

Two major pathological hallmarks of Alzheimer's disease (AD) are the senile plaques that are primarily composed of amyloid beta-peptide (Abeta) and neurofibrillary tangles consisting of tau aggregates. Abeta is generated proteolytically from a family of Abeta-containing precursor proteins (APP; 695-770 amino acid) by secretase enzymes to different specific carboxyl-terminal fragments (CTFs). Herein we examined APP and its products in autopsied brain sections from 10 AD and 10 non-AD control subjects immunochemically using an antibody that was raised against APP751-770 residue (O443). The O443 antibody was initially characterized by Western blot analysis and immunoprecipitation. In this study, we used this antibody for immunohistochemical analysis to determine the distribution of APP and its CTF species. In 10 brain regions showing different levels of plaques and tangles, antibody O443 stained the perinuclear region of the nucleus, plaques, and neurites. Tangle-bearing neurons also appeared to stain with the antibody, suggesting that these dysfunctional neurons continue to synthesize APP/CTF. Alternatively, the normally short-lived APP/CTF can be stabilized and persist in these neurons. Taken together, these results suggest that, in addition to the widely believed role of Abeta, CTFs may play a key role in the pathogenesis of AD. Studying their localization and biogenesis may reveal the biological activities of CTFs of APP. The present study may pave the way for possible antiamyloidogenic therapy in the treatment of AD.

Alzheimer Disease↗

PubMed2002

Functional characterization of the 5'-regulatory region of the murine apolipoprotein gene.

The apolipoprotein E (APOE) gene causes a major risk factor for the development of Alzheimer's disease (AD). To study the transcription control of the mouse (m) APOE gene, we first tested the promoter activity of a 721-base-pair (bp) 5'-flanking region, which is located 771 bp upstream from the translation initiation codon. We cloned the 721-bp region upstream of the reporter chloramphenicol acetyl transferase (CAT) gene into a promoterless vector (pBLCAT3). The mAPOE promoter and vector DNA were separately transfected in rat glial C6 and neuronal PC12 cell lines. The 721-bp APOE region (from position 329 to 1050) is functionally active in different cell lines tested. The serial deletion analysis indicates that the 266-bp promoter region (from 784 to 1050) has the highest and the 67-bp region (from 983 to 1050) the lowest activity on the reporter gene in neuronal and astrocytic cell lines. These studies suggest that the 147-bp region (from 637 to 784) has a negative regulatory effect on the reporter gene. In the gel shift assay, the 67-bp region binds to a specific transcription factor(s) in PC12 nuclear extracts. Our results suggest that mAPOE can also be expressed in neuronal cells in addition to the astrocytic cells. Characterization of mAPOE promoter is important for the AD drug development discovery and APOE transgenic mice studies.

5' Untranslated Regions↗

PubMed2002

Regulation of promoter activity of the APP gene by cytokines and growth factors: implications in Alzheimer's disease.

One of the major pathological hallmarks of Alzheimer's disease (AD) is the presence of brain depositions of senile plaques that are primarily composed of potentially toxic amyloid beta-peptide (Abeta), which is generated from a family of Abeta-containing precursor proteins (APP; 695-770 amino acids). The role of inflammatory cytokines and growth factors has been implicated in the pathogenesis of AD. Our goal is to study the effects of these factors on the regulation of APP gene expression. Here we compared APP promoter activity in the presence of different growth factors and cytokines such as brain-derived neurotrophic factor (BDNF), interleukin (IL-1), nerve growth factor (NGF), neurotrofin-3 (NT-3), transforming growth factor (TGF-beta1), and tumor necrosis factor (TNF-alpha1). PC12 neuronal cells, which were treated separately with these agents, were transfected with the construct containing either 190 bp APP proximal promoter region (-46 to 144 bp with respect to the transcription start site [+1]), 94 bp APP 5'-untranslated region (UTR, +50 to 144) or other 5'-UTR-deleted regions. Each construct was cloned upstream of a reporter chloramphenicol acetyl transferase gene (CAT). The treatment of PC12 cells with NGF stimulated reporter activity in all constructs tested. The treatment of cells with BDNF, NT3, TGF-beta1, or TNF-alpha stimulated reporter activity in a promoter/UTR-specific manner. Transfection with the complete -46 to 144 region retained the maximum stimulatory activity for any treatment tested in PC12 cells. These results suggest that the regulatory elements of the APP gene respond to the stimulation of different growth factors, cytokines, and interleukins. This is consistent with the effects of the different growth factors, cytokines, and interleukins on APP message and protein levels.

5' Untranslated Regions↗

PubMed2001

Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development.

The reduction in levels of the potentially toxic amyloid-beta peptide (Abeta) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the Abeta precursor protein (betaAPP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces betaAPP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in betaAPP processing. Phenserine treatment resulted in decreased secretion of soluble betaAPP and Abeta into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of betaAPP protein expression by phenserine was posttranscriptional as it suppressed betaAPP protein expression without altering betaAPP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving extracellular signal-regulated kinase or phosphatidylinositol 3-kinase activation, nor was it associated with the anticholinesterase activity of the drug. Furthermore, phenserine reduced expression of a chloramphenicol acetyltransferase reporter fused to the 5'-mRNA leader sequence of betaAPP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces Abeta levels by regulating betaAPP translation via the recently described iron regulatory element in the 5'-untranslated region of betaAPP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1. This study identifies an approach for the regulation of betaAPP expression that can result in a substantial reduction in the level of Abeta.

5' Untranslated Regions↗

PubMed2001

A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly, characterised by widespread loss of central cholinergic function. The only symptomatic treatment proven effective to date is the use of cholinesterase (ChE) inhibitors to augment surviving cholinergic activity. ChE inhibitors act on the enzymes that hydrolyse acetylcholine (ACh) following synaptic release. In the healthy brain, acetylcholinesterase (AChE) predominates (80%) and butyrylcholinesterase (BuChE) is considered to play a minor role in regulating brain ACh levels. In the AD brain, BuChE activity rises while AChE activity remains unchanged or declines. Therefore both enzymes are likely to have involvement in regulating ACh levels and represent legitimate therapeutic targets to ameliorate the cholinergic deficit. The two enzymes differ in location, substrate specificity and kinetics. Recent evidence suggests that BuChE may also have a role in the aetiology and progression of AD beyond regulation of synaptic ACh levels. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine, MF-8622) and ChE inhibitors such as rivastigmine, which have a dual inhibitory action on both AChE and BuChE, indicate potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. The development of specific BuChE inhibitors and the continued use of ChE inhibitors with the ability to inhibit BuChE in addition to AChE should lead to improved clinical outcomes.

Alzheimer Disease↗