A simplified representation of the data from the BrainPharm database (part of the SenseLab project). Disease process 82388 This work was the first to show different effects of donepezil on two different types of potassium channels (I K(DR) and I K(A)) of molluscan neurons. At a low concentration (5 uM), the drug suppressed I K(DR) but augmented I K(A); at higher concentrations (10-100 uM), it reduced both current types. The ability of donepezil to reduce I K(DR) at low concentrations suggests the drug ability to prevent neurodegeneration in Alzheimer's disease. (Solntseva et al., 2005) Disease process 68442 In voltage-clamp experiments with the myelinated nerve fibre of Xenopus laevis, 9-amino-1,2,3,4-tetrahydroacridine (THA) decreased both Na+ and K+ currents and shifted the steady state inactivation potential curve in a negative direction. The effects may be described as (a) a decrease of the permeability constant PNa, (b) a modified potential dependence of the inactivating system and (c) a decrease of PK. The Na+ system was affected more than the K+ system (Elinder F, et al. 1989) Disease process Disease process 66253 Experimental findings suggest that verapamil, an L-type (VDCC) calcium channel blocker may be useful in the cognitive deficits associated with AD (Freir DB et al. 2003) Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (A beta) is involved in Alzheimer's disease (AD), a neurode-generative disorder leading to cognitive deficits. Nicotine is also claimed to act as a cognitive enhancer. A beta is known to bind with high affinity to the alpha 7-nicotinic acetylcholine receptor (nAChR). ... (Experiments) demonstrate that nicotine enhances the deficit in LTP produced by A beta 1-40. This then suggests that nicotine may exacerbate the depressive actions of A beta on synaptic plasticity in AD. (Freir DB, Herron CE 2003) Disease process 66757 Disease process 66754 Areas of the brain affected in the early stages of Alzheimer's disease are also areas heavily involved in the processing of olfactory information. Olfactory event-related potentials (OERPs) and auditory ERPs were recorded from the Fz, Cz, and Pz electrode sites in 12 Alzheimer's disease (AD) patients and 12 age and gender matched normal controls (NC) in a single-stimulus paradigm with a 45 s inter-trial interval, using amyl acetate as the olfactory stimulus, and in a separate session a 500 Hz tone as the auditory stimulus. Odor identification (ID) was also used to assess ability to identify odors. The results indicate that (1) OERP P2 and P3 latencies were significantly longer in AD patients than normal controls; (2) olfactory ERP latency measures correlated significantly with dementia status as measured by the Dementia Rating Scale (DRS), indicating that as participants performed more poorly on the DRS, reflecting increased dementia, OERP latencies increased; (3) olfactory ERP latency measures better differentiated AD patients from normal controls than auditory ERP latency measures; (4) olfactory ERP measures alone correctly classified up to 92% of participants; (5) odor ID measures, namely the UPSIT and San Diego-Odor-ID tests also classified participants at a high rate. Combining scores for odor identification with olfactory P3 latency measures resulted in a correct classification rate of 100%. The results strongly support the use of olfactory measures in the assessment of AD. (Morgan CD, Murphy C 2002) Disease process 68441 "... (A study) suggests that degeneration of the LC noradrenergic system and the cholinergic cells of the basal forebrain have different functional consequences during the progression of AD. Finally, a combined treatment with noradrenergic and cholinergic drugs might produce a qualitatively broader effect on cognitive functions than either of the treatments alone, and more effectively attenuate clinical dementia" (Riekkenin P and Riekkenin M 1999). Disease process 66755 "Control of neuronal spiking patterns resides, in part, in the type and degree of expression of voltage-gated K(+) channel subunits. Abeta is a modulator of Kv4 subunit expression in neurones at both the functional and the molecular level. Thus Abeta is not only involved in Alzheimer pathology, but is also an important physiological regulator of ion channel expression and hence neuronal excitability." (Plant LD et al. 2005) Disease process 82412 Dentate gyrus granule cells have 37% dendritic extent reduction in AD compared to healthy controls (Anderton et al 1998). There is support for the hypothesis that this is due to the loss of afferent input from the entorhinal cortex (Diekmann et al. 1996, Einstein et al. 1994). The CA1-subiculum projection has a similar pathology (Anderton et al 1998) Disease process 74297 "p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro. ... Results show that sAbeta(1-42) at relatively low levels (1-5 microM) dose-dependently increases tau phosphorylation at AD-specific phosphoepitopes in differentiated N2a/p35 cells compared with controls, an effect that is blocked by antisense oligonucleotides against p35. sAbeta(1-42)-induced tau phosphorylation is concomitant with an increase in both p25 to p35 ratio and Cdk5 activity (but not protein levels). Additionally, blockade of L-type calcium channels or inhibition of calpain completely abolishes this effect." (Town et al. 2002) Disease process 82408 The evoked synaptic response of neurons to transcallosal stimuli is severely impaired in cortex containing substantial plaque accumulation, with an average 2.5-fold greater rate of response failure and twofold reduction in response precision compared with age-matched nontransgenic controls. ... results show that plaques disrupt the synchrony of convergent inputs, reducing the ability of neurons to successfully integrate and propagate information. (Stern et al. 2004) Early phase of Alzheimer pathological process Disease process 66753 OBJECTIVE: Recent research has demonstrated that individuals with Down's syndrome (DS) develop plaques and tangles in the brain similar to people with Alzheimer's disease. As a result, they show increased dementia and decreased olfactory functioning compared to healthy individuals. The olfactory event-related potential (OERP) has been used as an objective quantitative measure of olfactory functioning in normal and clinical populations. The present study investigated the utility of the latency and amplitude of the OERP components in examining olfactory dysfunction in DS individuals. METHODS: OERPs were recorded monopolarly at the Fz, Cz and Pz electrode sites, using amyl acetate at a 60 s inter-stimulus interval, from individuals with DS (mean age 26.0 years) and age-matched normal controls. Participants were screened for nasal health and odor thresholds were assessed. Dementia was assessed using the dementia rating scale (DRS). RESULTS: Results indicate that DS subjects have significantly longer latencies in the sensory (N1, P2, and N2) and cognitive (P3) components of the OERP than normal controls. Odor threshold was significantly associated with sensory OERP components. In addition, DS subjects with a higher level of dementia showed significantly longer P3 latencies than those with lower dementia levels. CONCLUSIONS: The study suggests that the OERP may be a useful measure of olfactory dysfunction in DS which may precede developing dementia in this population. (Wetter S, Murphy C 1999) Disease process 74656 Presenilins 1 and 2 (PS1 and PS2, respectively) play a critical role in mediating gamma-secretase cleavage of the amyloid precursor protein (APP). Numerous mutations in the presenilins are known to cause early-onset familial Alzheimer's disease (FAD). In addition, it is well established that PS1 deficiency leads to altered intracellular Ca(2+) homeostasis involving endoplasmic reticulum Ca(2+) stores. However, there has been little evidence suggesting Ca(2+) signals from extracellular sources are influenced by PS1. Here we report that the Ca(2+) currents carried by voltage-dependent Ca(2+) channels are increased in PS1-deficient cortical neurons. This increase is mediated by a significant increase in the contributions of L- and P-type Ca(2+) channels to the total voltage-mediated Ca(2+) conductance in PS1 (-/-) neurons. (Cook et al. 2005) Disease process 82365 Transgenic mice Alzhiemers models and hippocampal slice preparations from wild type rats support the Abeta Alzheimers hypothesis: that Abeta is a primary cause of Alzheimers (reviewed in Rowan et al 2003). Various transgenic mice show inhibition in LTP before amyloid plaques are deposited (Larson et al. 1999, Giacchino et al. 2000, Hsia et al. 1999, Chapman et al. 1999, Fitzjohn et al.2000, Moechars et al. 1999,Dewachter et al. 2002). Normal rat electrophysiology in hippocampal slices show that soluble 500 nM Abeta inhibits LTP induction (Lambert et al. 1998, Wang et al. 2002). These findings support the hypothesis that soluble Abeta disrupts synaptic plasticity in the hippocampus in early Alzheimers before Abeta plaques form. Disease process 66751 We present intracellular data which demonstrates a unique facilitatory centrifugal influence on the output cells of the olfactory bulb; the source being the lateral component of the nucleus of the horizontal limb of the diagonal band (HDB), part of the basal forebrain magnocellular complex. Damage to this facilitatory HDB influence may explain the loss of olfactory sensitivity seen early in Alzheimer's disease in which pathological changes occur in the basal forebrain. (Kunze WA et al. 1992) Phase of Alzheimer pathological process Disease process 66281 The role of the voltage-sensitive Ca2+ channel (VSCC) in beta (25-35) neurotoxicity was examined using rat cultured cortical and hippocampal neurons. When L-type VSCCs were blocked by application of nimodipine, beta (25-35) neurotoxicity was attenuated, whereas application of omega-conotoxin GVIA (omega-CgTX-GVIA) or omega-agatoxin IVA (omega-Aga-IVA), the blocker for N- or P/Q-type VSCCs, had no effects. Whole-cell patch-clamp studies indicated that the Ca2+ current density of beta (25-35)-treated neurons is about twofold higher than that of control neurons. Also, beta (25-35) increased Ca2+ uptake, which was sensitive to nimodipine. The 2', 7'-dichlorofluorescin diacetate assay showed the ability of beta (25-35) to produce reactive oxygen species. Nimodipine had no effect on the level of free radicals. In contrast, vitamin E, a radical scavenger, reduced the level of free radicals, neurotoxicity, and Ca2+ uptake. These results suggest that beta (25-35) generates free radicals, which in turn, increase Ca2+ influx via the L-type VSCC, thereby inducing neurotoxicity. (Ueda K et al. 1997) Disease process 66815 The channel hypothesis of Alzheimer's disease (AD) proposes that the beta-amyloid (Abeta) peptides which accumulate in plaques in the brain actually damage and/or kill neurons by forming ion channels. Evidence from a number of laboratories has demonstrated that Abeta peptides can form ion channels in lipid bilayers, liposomes, neurons, oocyctes, and endothelial cells. These channels possess distinct physiologic characteristics that would be consistent with their toxic properties. Abeta channels are heterogeneous in size, selectivity, blockade, and gating. They are generally large, voltage-independent, and relatively poorly selective amongst physiologic ions, admitting calcium ion (Ca(2+)), Na(+), K(+), Cs(+), Li(+), and possibly Cl(-). They are reversibly blocked by zinc ion (Zn(2+)), and tromethamine (tris), and irreversibly by aluminum ion (Al(3+)). Congo red inhibits channel formation, but does not block inserted channels. Although much evidence implicates Abeta peptides in the neurotoxicity of AD, no other toxic mechanism has been demonstrated to be the underlying etiology of AD. Channel formation by several other amyloid peptides lends credence to the notion that this is a critical mechanism of cytotoxicity. Alzheimer pathological process Disease process 66248 A model shows that block of I_A is sufficient to cause membrane depolarization, calcium influx, and increased excitability (Good TA, Murphy RM 1996). Disease process 68443 ... the selective L-VSCC (L-type volt. sens. Ca chan.) agonist Bay K8644 increased the afterhyperpolarization and mimicked the depressive effects of aging on FF (frequency facilititation) in young-adult neurons. Thus, during physiologically relevant firing patterns in aging neurons, postsynaptic Ca(2+) elevation is closely associated with altered neuronal plasticity. Moreover, selectively increasing postsynaptic L-VSCC activity, as occurs in aging, negatively regulated a form of short-term plasticity that enhances synaptic throughput. Together, the results elucidate novel processes that may contribute to impaired cognitive function in aging (Thibault O, et al. 2001). Disease process 66240 Application of beta-amyloid to outside-out patches reduces the A-current; leading to increased dendritic calcium influx and loss of calcium homeostasis, potentially causing synaptic failure and initiating neuronal degenerative proceses(Chen C 2005). Disease process 74290 Prior studies indicate that one of the kinases that phosphorylates tau (mitogen-activated protein kinase, or MAP kinase) does so at least in part indirectly within intact neuronal cells by phosphorylating and activating the L-voltage-sensitive calcium channel. Resultant calcium influx then fosters tau phosphorylation via one or more calcium-activated kinases. okadaic acid (OA) similarly may increase tau phosphorylation via sustained activation of the L-voltage-sensitive calcium channel. OA increased phospho-tau as indicated by increased immunoreactivity towards an antibody (PHF-1) directed against paired helical filaments from AD brain. This increase was blocked by co-treatment with the channel antagonist nimodipine. ... Okadaic acid (OA) treatment increased channel phosphorylation. The increases in calcium influx, PHF-1 immunoreactivity and channel phosphorylation were all attenuated by co-treatment with PD98059, which inhibits MAP kinase activity, suggesting that OA mediates these effects at least in part via sustained activation of MAP kinase. (Ekinci FJ et al. 2003) Disease process 66756 A reduced level of LTP could still be recorded following co-administration of verapamil and D-AP5. The level of LTP recorded was similar to that observed in the presence of either verapamil (10 mg/kg) or D-AP5 alone. These results suggest that activation of the NMDA receptor/channel and L-type VDCCs are involved in the induction of LTP in area CA1 in vivo. However, it appears that activation of other receptor/channels may also play a role in this form of LTP. (Freir DB, Herron CE 2003) Disease process 82741 "The effect of AF267B on cognition predicted the neuropathological outcome, as both the Abeta and tau pathologies were reduced in the hippocampus and cortex, but not in the amygdala." (Caccamo et al. 2006) Pathological process Disease process 82372 ... to examine the effect of donepezil on Abeta(1-40) induced neurotoxicity in primary cultures of rat septal neurons. Using immunohistochemical staining, almost all the neurons were found to be positive for vesicular acetylcholine transporter (VAChT) in these septal cultures. Septal neuronal cells were cultured for 7 days and then 15 micromol/L of Abeta(1-40) was added to the cell medium for 48 h. The cultured septal neurons were highly susceptible to Abeta toxicity, as shown by morphological examination and lactate dehydrogenase (LDH) assay. Donepezil concentration-dependently reduced the LDH efflux induced by Abeta(1-40), and the effect was significant at 100 nmol/L and above. Donepezil decreased both the negative peak at around 215 nm in the circular dichroism (CD) spectrum and the fluorescence intensity of thioflavin T in the presence of Abeta(1-40). These results suggest that donepezil exerts a neuroprotective effect by reducing the amount of the toxic form of Abeta fibrils in septal neuron cultures. These findings support the idea that the clinical efficacy of donepezil in AD is due to not only activation of cholinergic transmission, but also attenuation of neuronal damage. (Kimura et al., 2005) "The toxicity of beta-Amyloid(25-35) implicates a potentiation of L-type Ca currents while the one of beta-Amyloid(1-40) is related to an increase of non-L-type Ca channels ..." (Rovira C, et al. 2002). Disease process 66249 Disease process 82409 Protofibrils, but not (Light Molecular Weight) Abeta, produced a rapid increase in EPSPs, action potentials, and membrane depolarizations (and neurotoxicity) in cultured neurons from rat embryo brain. (Hartley et al. 1999) Phase of pathological process Disease process 66752 Electrical stimulation of the horizontal limb of the diagonal band evoked negative potentials in the granule cell layer. Neurons in the granule cell layer were excited, and those in the mitral cell layer and external plexiform cell layer showed inhibition, often followed by excitation. (Inokuchi A et al. 1987) Although single shocks to HDB have little effect upon function of the target structure, short periods of repetitive stimulation produce profound changes. These observations are discussed in terms of the known physiology of central cholinergic systems and the significance of cholinergic synaptic potentiation for Alzheimer's disease. (Nickell WT, Shipley MT 1987) Disease process 74294 Huperzine A inhibits A current and sustained potassium current in dissociated hippocampal neurons. (Li and Hu 2002, Li and Hu 2002). Early phase of pathological process Disease process 66252 "(Our experimental) findings indicate that redirection rather than increased activation of MAP-Kinase activity mediates beta_Amyloid-induced neurotoxicity." (Ekinci FJ et al. 1999). Disease process 66251 Experiments with double knockin mice suggest that AMPARs are important synaptic targets for AD and provide evidence that cognitive impairment may involve downscaling of postsynaptic AMPAR function (Chang EH et al. 2006) Disease process 66758 "The effect of intracerebroventricular (icv) injections of beta-amyloid peptide fragments Abeta[15-25], Abeta[25-35], and Abeta[35-25] were examined on synaptic transmission and long-term potentiation (LTP) in the hippocampal CA1 region in vivo. ... LTP was, however, markedly reduced by Abeta[25-35; 10 nmol] (129 +/- 9%, n = 6, P < 0.001) and blocked by Abeta[25-35; 100 nmol] (99 +/- 6%, n = 6, P < 0.001). ... The Abeta-peptides tested were also shown to have no significant effect on paired pulse facilitation (interstimulus interval of 50 ms), suggesting that neither presynaptic transmitter release or activity of interneurons in vivo are affected. The effects of Abeta on LTP are therefore likely to be mediated via a postsynaptic mechanism. This in vivo model of LTP is extremely sensitive to Abeta-peptides that can impair LTP in a time- ([25-35]) and concentration-dependent manner ([25-35] and [35-25]). These effects of Abeta-peptides may then contribute to the cognitive deficits associated with Alzheimer's disease." (Freir DB et al. 2001) Disease process 66750 " ... aluminum can alter the function of GABAA receptors and may suggest that aluminum can contribute to cognitive impairment through disruption of inhibitory circuits." (Trombley PQ 1998) Disease process 66250 Impairment of LTP by beta-Amyloid is independent of NMDA receptors or voltage dependent Ca currents (Nomura I et al. 2005)