Pathological mechanism (s) having Alzheimer as Pathology

1 "...beta-Amyloid(1-40) is related to an increase of non-L-type Ca channels ..." (Rovira C, et al. 2002).
2 "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)
3 "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)
4 "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)
5 A beta(3)-AR agonist (CL316243), but not a beta(2)-AR agonist, rescued Abeta-induced memory loss in chicks given an intra-cranial injection of Abeta42. Memory loss caused by beta-amyloid protein is rescued by a beta(3)-adrenoceptor agonist.Gibbs ME, Maksel D, Gibbs Z, Hou X, Summers RJ, Small DH. Neurobiol Aging. 2008 Jul 14
6 A model shows that block of I_A is sufficient to cause membrane depolarization, calcium influx, and increased excitability (Good TA, Murphy RM 1996).
7 A review of loss or alteration of dendritic spines induced by the amyloid beta (Abeta) peptide in the context of AD. Dendritic spine loss and synaptic alterations in Alzheimer's disease.Knobloch M, Mansuy IM. Mol Neurobiol. 2008 Feb;37(1):73-82.
8 Abeta blocks voltage-gated Na+ channels in GABA neurons causing abberant excitation in hAPP transgenic mice, that have cognitive deficits similar to AD. This seizure-like activity may lead to inhibitory mechanisms that produce cognitive deficits. Alzheimer's and Dementia Supplement, 2008 (ICAD meeting). Palop JJ, Thwin, Ho, Yu and Mucke
9 Abeta inhibits nicotinic ACh receptors at pre-synaptic glutamatergic terminals, causing failure of nicotine-dependent enhancement of synaptic efficacy at Schaffer-collateral CA1 synapses of AD11 anti-nerve growth factor transgenic mice. This takes place possibly through calcium signalling via presynaptic alpha7 nicotine acetylcholine receptors. Sola E, Capsoni S, Rosato-Siri M, Cattaneo A, Cherubini E. Eur J Neurosci. 2006 Sep;24(5):1252-64
10 Abeta1-40 peptide in soluble and fibrillar forms (beta pleated sheets) that are morphologically distinct can both attenuate hippocampal long-term potentiation (LTP) in the CA1 in vivo. The fibrillar form may also influence transmitter release.Schmid, A. W., Freir, D. B., & Herron, C. E. (2008). Inhibition of LTP in vivo by beta-amyloid peptide in different conformational states. Brain Res, 1197, 135-142.
11 Abeta42/Abeta40 ratio correlates with impaired LTP and with dendritic spine density and behavioral competence in the Tg2576 mouse model of AD. This happens before there is any significant increase in beta amyloid levels. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease.Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. Proc Natl Acad Sci U S A. 2006 Mar 28, 103(13):5161-6.
12 ADDL binding instigates synapse loss, oxidative damage, and AD-type tau hyperphosphorylation.ADDLs act as pathogenic gain-of-function ligands that target particular synapses, binding to synaptic spines at or near NMDA receptors. Subsequent ADDL-induced abnormalities in spine morphology and synaptic receptor composition. Viola, K. L., Velasco, P. T., & Klein, W. L. (2008). Why alzheimer's is a disease of memory: The attack on synapses by A beta oligomers (addls). The Journal of Nutrition, Health & Aging, 12(1), 51S-57S.
13 Akram, A., Christoffel, D., Rocher, A. B., Bouras, C., Kövari, E., Perl, D. P., et al. (2007). Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of alzheimer's disease. Neurobiol Aging, , Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. Data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.
14 Amyloid beta peptide adversely affects spine number and motility in hippocampal neurons.Shrestha BR, Vitolo OV, Joshi P, Lordkipanidze T, Shelanski M, Dunaevsky A. Mol Cell Neurosci. 2006 Nov;33(3):274-82. Exposure of hippocampal neurons to sub-lethal levels of Abeta decreased spine density, increased spine length and subdued spine motility. The effect of Abeta on spine density was reversible. Moreover, Abeta's effect on dendritic spine density was blocked by rolipram, a phosphodiesterase type IV inhibitor.
15 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).
16 BACE1 knock-out mice display reduced presynaptic function at the mossy fiber projections in CA3. Mossy fiber long-term potentiation (LTP), which is normally expressed via an increase in presynaptic release, was eliminated in the knock-outs. The specific deficit in mossy fiber LTP was upstream of cAMP signaling and could be "rescued" by transiently elevating extracellular Ca2+ concentration. These results suggest that BACE1 may play a critical role in regulating presynaptic function, especially activity-dependent strengthening of presynaptic release, at mossy fiber synapses. BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus.Wang H, Song L, Laird F, Wong PC, Lee HK. J Neurosci. 2008 Aug 27;28(35):8677-81.
17 Bramham, C. R. (2007). Control of synaptic consolidation in the dentate gyrus: Mechanisms, functions, and therapeutic implications. Progress in Brain Research, 163, 453-471. Dysregulation of BDNF synthesis and Arc function, specifically within the dentate gyrus, is linked to behavioral symptoms and cognitive deficits in animal models of depression and Alzheimer's disease.
18 Calabrese, B., Shaked, G. M., Tabarean, I. V., Braga, J., Koo, E. H., & Halpain, S. (2007). Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein. Molecular and Cellular Neurosciences, 35(2), 183-193. Within 1-2 h picomolar concentrations of cell-derived, soluble Abeta cause Clusters of presynaptic vesicle markers to decrease in size and number at glutamatergic but not GABAergic terminals. Dendritic spines also decreased in number and became dysmorphic, as spine heads collapsed and/or extended long protrusions. Simultaneous time-lapse imaging of axon-dendrite pairs revealed that shrinking spines sometimes became disconnected from their presynaptic varicosity. Concomitantly, miniature synaptic potentials decreased in amplitude and frequency. Spine changes were prevented by blockers of nAChRs and NMDARs. Washout of Abeta within the first day reversed these spine changes.
19 Chronic nicotine improves working and reference memory performance and reduces hippocampal NGF in aged female rats.French KL, Granholm AC, Moore AB, Nelson ME, Bimonte-Nelson HA. Behav Brain Res. 2006 May 15;169(2):256-62 There is a nicotine-induced reduction in nerve growth factor (NGF) protein levels in the hippocampus of the aged rat. Nicotine improved the ability to handle an increasing working memory load as well as enhanced performance on the reference memory component of the water radial arm maze task.
20 Counts, S. E., Nadeem, M., Lad, S. P., Wuu, J., & Mufson, E. J. (2006). Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. Journal of Neuropathology and Experimental Neurology, 65(6), 592-601. Levels of DRB, a dendritic spine plasticity marker, were reduced approximately 40% to 60% in all cortical regions in AD compared with normals.In contrast, DRB levels in the superior frontal cortex increased approximately 30% in AD subjects.
21 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)
22 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)
23 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)
24 Impairment of LTP by beta-Amyloid is independent of NMDA receptors or voltage dependent Ca currents (Nomura I et al. 2005)
25 Ji, Y., Gong, Y., Gan, W., Beach, T., Holtzman, D. M., & Wisniewski, T. (2003). Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and alzheimer's disease patients. Neuroscience, 122(2), 305-315. Human apoE3 and WT mice had a higher density of dendritic spines than human E4 and apoE KO mice in the 1 and 2 year age groups. In human brain, apoE4 dose correlated inversely with dendritic spine density of DG neurons cell in the hippocampus of both AD (P=0.0008) and aged normal controls (P=0.0015).
26 Johnston, D., Hoffman, D. A., Colbert, C. M., & Magee, J. C. (1999). Regulation of back-propagating action potentials in hippocampal neurons. Current Opinion in Neurobiology, 9(3), 288-292. Protein kinase C modulates the slow recovery from inactivation of Na+ channels in apical dendrites of hippocampal CA1 pyramidal neurons. Dendritic, A-type K+ channels have been found to be modulated by protein kinases A and C and by mitogen-activated protein kinase.
27 Ligands that neutralize TNFalpha or genetic knockout of TNF-R1s (type-1 TNFalpha receptors) prevented Abeta-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to alphav-containing integrins abrogated LTP block by Abeta.Mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction long before widespread synaptic loss and neurodegeneration occurs. Rowan, M. J., Klyubin, I., Wang, Q., Hu, N. W., & Anwyl, R. (2007). Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochemical Society Transactions, 35(Pt 5), 1219-1223.
28 Only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses reveals very powerful correlations withpsychological assays in AD/normal subjects. Midfrontal and inferior parietal synapse density, plus inferior parietal plaque has a correlation coefficient of 0.96 with Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength.
29 Pocivavsek, A., Icenogle, L., & Levin, E. D. (2006). Ventral hippocampal alpha7 and alpha4beta2 nicotinic receptor blockade and clozapine effects on memory in female rats. Psychopharmacology, 188(4), 597-604. The state of nicotinic receptor activation in the ventral hippocampus significantly affected the impact of clozapine on working memory with blockade of alpha7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of alpha4beta2 receptors reversing the clozapine effect from impairing to improving memory.
30 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)
31 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)
32 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)
33 Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior.Selkoe DJ. Behav Brain Res. 2008
34 Spencer, J. P., Weil, A., Hill, K., Hussain, I., Richardson, J. C., Cusdin, F. S., et al. (2006). Transgenic mice over-expressing human beta-amyloid have functional nicotinic alpha 7 receptors. Neuroscience, 137(3), 795-805. Amyloid beta peptide(1-42) antagonized human alpha7 responses in a partially reversible fashion; no agonist effects were detected. A similar inhibition of mouse alpha 7 was also observed. Hippocampal GABAergic interneurones in slices from beta-amyloid over-expressing mice still possess alpha 7 receptor-mediated currents.
35 Synaptic plasticity in animal models of early Alzheimer's disease.Rowan MJ, Klyubin I, Cullen WK, Anwyl R. Philos Trans R Soc Lond B Biol Sci. 2003 Apr 29;358(1432):821-8.
36 The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 i.c.v.-injected mice: involvement of dopaminergic systems.Wang D, Noda Y, Zhou Y, Mouri A, Mizoguchi H, Nitta A, Chen W, Nabeshima T. Neuropsychopharmacology. 2007 Jun;32(6):1261-71. Galantamine augments dopaminergic neurotransmission within the hippocampus through the allosteric potentiation of nAChRs. The improving-effects of galantamine on the Abeta(25-35)-induced cognitive impairment may be mediated through the activation of, at least in part, dopaminergic systems
37 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.
38 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)
39 The opening of the Alzheimer's Abeta channel permits the flux of calcium into the cell, thus critically disturbing intracellular ion homeostasis. Peptide segments which include the characteristic histidine diad, His13 and His14, efficiently block the Abeta channel activity blocking Abeta cytotoxicity. Compounds that are known to have histidine association capacity, such as Ni(2+), imidazole, histidine and a series of histidine-related compounds were effective at blocking both Abeta channels and preventing Abeta cytotoxicity. The efficiency of protection of histidine-related compounds was correlated with the number of imidazole side chains in the blocker compounds. Efficiency of histidine-associating compounds for blocking the Alzheimer's A{beta} channel activity and cytotoxicity.Arispe NJ, Diaz JC, Flora M. Biophys J. 2008 Aug 22.
40 The study investigated the effects of elevated soluble Abeta on neuronal morphology in mutant human amyloid precursor protein (hAPP) transgenic mice somatosensory pyramidal cells. Basal arbors were unaffected, but apical arbors were shortened in total length and less branched. The diameter of proximal dendritic segments was increased whereas that of distal segments was reduced. There was a significant reduction in spine densities along the whole course of dendrites.