ß amyloid protein precursor-like
Amyloid beta peptide (Abeta), a proteolytic fragment of the amyloid precursor protein (APP), is a major component of the plaques found in the brain of Alzheimer's disease (AD) patients. These plaques are thought to cause the observed loss of cholinergic neurons in the basal forebrain of AD patients. In these neurons, particularly those of the nucleus basalis of Meynert, an up-regulation of 75kD-neurotrophin receptor (p75NTR), a nonselective neurotrophin receptor belonging to the death receptor family, has been reported. p75NTR expression has been described to correlate with beta-amyloid sensitivity in vivo and in vitro, suggesting a possible role for p75NTR as a receptor for Abeta. A human neuroblastoma cell line to investigate the involvement of p75NTR in Abeta-induced cell death. Abeta peptides were found to bind to p75NTR resulting in activation of NFKB in a time- and dose-dependent manner. Blocking the interaction of Abeta with p75NTR using NGF or inhibition of NFKB activation by curcumin or NFKB SN50 attenuates or abolishes Abeta-induced apoptotic cell death. The present results suggest that p75NTR might be a death receptor for Abeta, thus being a possible drug target for treatment of AD (Kuner, 1998).
In several pedigrees of early onset familial Alzheimer's disease (FAD), point mutations in the beta-amyloid precursor protein (APP) gene are genetically linked to the disease. This finding implicates APP in the pathogenesis of Alzheimer's disease in these individuals. To understand the in vivo function of APP and its processing, an APP-null mutation has been generated in mice. Homozygous APP-deficient mice are viable and fertile. However, the mutant animals weigh 15%-20% less than age-matched wild-type controls. Neurological evaluation shows that the APP-deficient mice exhibit a decreased locomotor activity and forelimb grip strength, indicating a compromised neuronal or muscular function. In addition, four out of six homozygous mice show reactive gliosis at 14 weeks of age, suggesting an impaired neuronal function as a result of the APP-null mutation (Zheng, 1995).
The Alzheimer's beta-amyloid precursor protein (beta-APP) is widely expressed in neural cells. In neurons, secreted forms of beta-APP (sAPPs) are released from membrane-spanning holo-beta APP in an activity-dependent manner. Secreted APPs can modulate neurite outgrowth, synaptogenesis, synaptic plasticity and cell survival; a signal transduction mechanism of sAPPs may involve modulation of intracellular calcium levels ([Ca2+]i). Whole-cell perforated patch and single-channel patch-clamp analysis of hippocampal neurons was used to demonstrate that sAPPs suppress action potentials and hyperpolarize neurons by activating high-conductance, charybdotoxin-sensitive K+ channels. Activation of K+ channels by sAPPs is mimicked by a cyclic GMP analog and sodium nitroprusside and blocked by an antagonist of cGMP-dependent kinase and a phosphatase inhibitor, suggesting that the effect is mediated by cGMP and protein dephosphorylation. Calcium imaging studies indicate that activation of K+ channels mediates the ability of sAPPs to decrease [Ca2+]i. Modulation of neuronal excitability may be a major mechanism by which beta-APP regulates developmental and synaptic plasticity in the nervous system (Furukawa, 1996).
The secreted form of beta-amyloid precursor protein (sAPP alpha) is released from neurons in an activity-dependent manner: data suggest sAPP alpha may play roles in regulating neuronal excitability, plasticity, and survival. In cultured hippocampal neurons sAPP alpha can suppress elevation of [Ca2+]i induced by glutamate and can protect neurons against excitotoxicity. Whole-cell patch-clamp data from studies of cultured embryonic rat hippocampal neurons demonstrate that sAPP alpha selectively suppresses N-methyl-D-aspartate currents without affecting currents induced by AMPA or kainate. sAPP alpha suppresses N-methyl-D-aspartate current rapidly and reversibly at concentrations of 0.011 nM. Suppression of N-methyl-D-aspartate current by sAPP alpha is apparently mediated by cyclic guanosine monophosphate because 8-bromo-cyclic guanosine monophosphate suppresses N-methyl-D-aspartate current in a manner similar to sAPP alpha, and two different inhibitors of cyclic guanosine monophosphate-dependent protein kinase prevent sAPP alpha-induced suppression of N-methyl-D-aspartate current. In addition, okadaic acid prevents suppression of N-methyl-D-aspartate-induced current, suggesting the involvement of a protein phosphatase in modulation of N-methyl-D-aspartate current by sAPP alpha. These data identify a mechanism whereby sAPP alpha can modulate cellular responses to glutamate, and suggest important roles for sAPP alpha in the various physiological and pathophysiological processes in which N-methyl-D-aspartate receptors participate (Furukawa, 1998).
The secreted form of amyloid precursor protein (sAPPalpha), which is released from neurons in an activity-dependent manner, can modulate neurite outgrowth, synaptic plasticity, and neuron survival. sAPPalpha can enhance glucose and glutamate transport in synaptic compartments. Treatment of cortical synaptosomes with nanomolar concentrations of sAPPalpha results in an attenuation of impairment of glutamate and glucose transport induced by exposure to amyloid beta-peptide and Fe2+. The protective effect of sAPPalpha is mimicked by treatment with 8-bromo-cyclic GMP and blocked by a cyclic GMP-dependent protein kinase inhibitor, suggesting that protective action of sAPPalpha is mediated by cyclic GMP. These data suggest that glucose and glutamate transport can be regulated locally at the level of the synapse and further suggest important roles for sAPPalpha and cyclic GMP in modulating synaptic physiology under normal and pathophysiological conditions (Mattson, 1999).
The amyloid precursor superfamily is composed of three highly conserved transmembrane glycoproteins, the amyloid precursor protein (APP) and amyloid precursor-like proteins 1 and 2 (APLP1, APLP2), whose functions are unknown. Proteolytic cleavage of APP yields the betaA4 peptide, the major component of cerebral amyloid in Alzheimer's disease. Five post-translationally modified, full-length species of APP and APLP2 (but not APLP1) arrive at the mature presynaptic terminal in the fastest wave of axonal transport and are subsequently rapidly cleared (mean half-life of 3.5 h). Rapid turnover of presynaptic APP and APLP2 occurs independently of visual activity. Turnover of the most rapidly arriving APP species is accompanied by a delayed accumulation of a 120-kDa, APP fragment lacking the C terminus, consistent with presynaptic APP turnover via constitutive proteolysis. Turnover of APLP2 is not accompanied by detectable APLP2 fragment peptides, suggesting either that APLP2 either is more rapidly degraded than is APP or is retrogradely transported shortly after reaching the terminus. A single 150-kDa APLP2 species containing the Kunitz protease inhibitor domain is the major amyloid precursor superfamily protein transported to the presynapse. Presynaptic APP and APLP2 are sialylated and N- and O-glycosylated, and some also carry chondroitin sulfate glycosaminoglycan and/or dermatan sulfate glycosaminoglycan. The rapid kinetics for turnover of APP and APLP2 predict a sensitive balance of synthesis, transport, and elimination rates that may be critical to normal neuronal functions and metabolic fates of these proteins (Lyekman, 1998).
The beta-amyloid precursor protein (beta APP) gene of the mouse was disrupted by inserting into exon 2 a cassette containing a neomycin resistance gene and a putative transcription termination sequence. Contrary to expectation, brain and other tissues from mice homozygous for the insertion still contain beta APP-specific RNA, albeit at a level 5- to 10-fold lower than wild type and lacking the disrupted exon, which had been spliced out. The brain contained shortened beta APP-specific protein at a low level. Mutant mice are severely impaired in spatial learning and exploratory behavior and show increased incidence of agenesis of the corpus callosum (Muller, 1994).
To address the question of the actual function of APP in normal developing neurons, a study aimed at blocking APP expression using antisense oligonucleotides was undertaken. Oligonucleotide internalization was achieved by linking them to a vector peptide that translocates through biological membranes. This original technique, which is very efficient and gives direct access to the cell cytosol and nucleus, allowed for studies with extracellular oligonucleotide concentrations between 40 and 200 nM. Internalization of antisense oligonucleotides overlapping the origin of translation results in a marked but transient decrease in APP neosynthesis. Although transient, the decrease in APP neosynthesis is sufficient to provoke a distinct decrease in axon and dendrite outgrowth by embryonic cortical neurons developing in vitro. The latter decrease is not accompanied by changes in the spreading of the cell bodies. A single exposure to coupled antisense oligonucleotides at the onset of the culture is sufficient to produce significant morphological effects 6, 18, and 24 h later, but by 42 h, there are no remaining significant morphologic changes. This report thus demonstrates that amyloid precursor protein plays an important function in the morphological differentiation of cortical neurons in primary culture (Allinquant, 1995).
Alzheimer's amyloid precursor protein (APP), the precursor of beta-amyloid (Abeta), is an integral membrane protein with a receptor-like structure. The mature APP (mAPP; N- and O-glycosylated form) is phosphorylated at Thr668 (numbering for APP695 isoform), specifically in neurons. Phosphorylation of mAPP appears to occur during, and after, neuronal differentiation. The phosphorylation of mAPP begins 48-72 hr after treatment of PC12 cells with NGF and this correlates with the timing of neurite outgrowth. The phosphorylated form of APP is distributed in neurites and mostly in the growth cones of differentiating PC12 cells. PC12 cells stably expressing APP with Thr668Glu substitution show remarkably reduced neurite extension after treatment with NGF. These observations suggest that the phosphorylated form of APP may play an important role in neurite outgrowth of differentiating neurons (Ando, 1999).
The amyloid precursor protein (APP) and APP-like (APLP) material, as visualized with the Mab22C11 antibody, have been shown to be associated with radial glia in hypothalamus. Radial glia are known to promote neurite outgrowth. By Northern blot analysis, APP 695 mRNA levels increases steadily over hypothalamic development, APP 770 mRNA is transiently expressed at 12 days postnatally, and APLP mRNA is only weakly expressed in the hypothalamus. The developmental pattern of APP moeities in mouse hypothalamus and in fetal hypothalamic neurons in culture has been compared with a presenilin 2 (PS2) related protein using an antibody developed against the N-terminal part of PS2. By Western blot analysis, APP and PS2-like immunoreactivity are visualized as a 100-130kDa band and a 52 kDa band, respectively. An APP biphasic increase is observed during hypothalamic development in vivo. APP immunoreactivity is equally detected in neuronal and glial cultures, while PS2-like material is more concentrated in neurons. A correlation between APP/APP-like and PS2-like levels was observed during development in vivo. While APP is mostly associated with membrane fractions, a significant portion of PS2-like material is also recovered from cytosolic fractions in vitro. In contrast to native PS2 in COS-transfected cells, the PS2-like material does not aggregate after heating for 90 s at 90 degrees C. These results indicate a close association between APP and PS2-like material during hypothalamic development in vivo, and suggest that neuronal and glial cultures may provide appropriate models to test their interactions (Apert, 1998).
Amyloid deposition is a neuropathological hallmark of Alzheimer's disease. The principal component of amyloid deposits is beta amyloid peptide (Abeta), a peptide derived by proteolytic processing of the amyloid precursor protein (APP). APP is axonally transported by the fast anterograde component. Several studies have indicated that Abeta deposits occur in proximity to neuritic and synaptic profiles. Taken together, these latter observations have suggested that APP, axonally transported to nerve terminals, may be processed to Abeta at those sites. To examine the fate of APP in the CNS, [35S]methionine was injected into the rat entorhinal cortex and the trafficking and processing of de novo synthesized APP was examined in the perforant pathway and at presynaptic sites in the hippocampal formation. Both full-length and processed APP accumulate at presynaptic terminals of entorhinal neurons. At these synaptic sites, C-terminal fragments of APP containing the entire Abeta domain accumulate, suggesting that these species may represent the penultimate precursors of synaptic Abeta (Buxbaum, 1998).
The secreted form (sAPP) of the Alzheimer amyloid beta/A4 protein precursor (APP) has been shown to be involved in the in vitro regulation of fibroblast growth and neurite extension from neuronal cells. The active site of sAPP responsible for these functions is within a small domain just C-terminal to the Kunitz-type protease inhibitor (KPI) insertion site. A 17-mer peptide, containing this active domain of sAPP, can induce cellular and behavioral changes when infused into rat brains. After 2 weeks of APP 17-mer peptide infusion, the animals were tested for reversal learning and memory retention and were sacrificed for morphological examination of brains. Administration of the APP 17-mer peptide results in an 18% increase in the number of presynaptic terminals in the frontoparietal cortex. At the behavioral level, 17-mer-infused animals with nonimpaired learning capability show an increased memory retention that seems to interfere with reversal learning performance. This APP 17-mer effect on memory retention is not observed in animals with impaired initial learning capacity. These results suggest that APP is involved in memory retention through its effect on synaptic structure (Roch, 1994).
The secreted form of beta-amyloid precursor protein (sAPP alpha) is released from neurons in an activity-dependent manner, and has been reported to modulate neuronal excitability in dissociated hippocampal neurons. sAPP alpha shifts the frequency dependence for induction of long-term depression of synaptic transmission (LTD) in hippocampal slices from adult rats. Whereas low frequency stimulation (1 Hz) of Schaffer collateral axons induces LTD of the post-synaptic response of CA1 neurons in control slices, it does not induce LTD in slices pretreated with sAPP alpha. However, while a 10 Hz stimulation normally induces neither LTD or LTP, it does induce LTD in slices pretreated with sAPP alpha. sAPP alpha potentiates LTP induced by high frequency stimulation. sAPP alpha induces cGMP production in hippocampal slices, and pretreatment of slices with 8-bromo-cyclic GMP mimics the effect of sAPP alpha on LTD, suggesting a role for cyclic GMP in modulation of LTD. The data suggest an important role for sAPP alpha in the modulation of synaptic plasticity in the hippocampus (Ishida, 1997).
Abnormal processing of amyloid precursor protein (APP), in particular the generation of beta-amyloid (Abeta) peptides, has been implicated in the pathogenesis of Alzheimer's disease. This study examined the consequences of deleting the APP gene on hippocampal synaptic plasticity, and upon the biophysical properties of morphologically identified neurons in APP-null mice. The hippocampus of APP-null mice has a characteristic increase in gliosis throughout the CA1 region and a disruption of staining for the dendritic marker MAP2 and the presynaptic marker synaptophysin. The disruption of MAP2 staining is associated with a significant reduction in overall dendritic length and projection depth of biocytin labeled CA1 neurons. In two groups of APP-null mice examined at 8-12 months, and 20-24 months of age, there was an impairment in the formation of long-term potentiation (LTP) in the CA1 region, compared to isogenic age matched controls. This LTP deficit is not associated with an alteration in the amplitude of EPSPs at low stimulus frequencies (0.033 Hz) or facilitation during a 100 Hz stimulus train, but is associated with a reduction in post-tetanic potentiation. Paired-pulse depression of GABA-mediated inhibitory post-synaptic currents is also attenuated in APP-null mice. These data demonstrate that the impaired synaptic plasticity in APP deficient mice is associated with abnormal neuronal morphology and synaptic function within the hippocampus (Seabrook, 1999).
Synaptic communication and plasticity were investigated in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE). These mice show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit is correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients (Chapman, 1999).
A presenilin-1 (PS1) conditional knockout mouse (cKO) has been generated in which PS1 inactivation is restricted to the postnatal forebrain. The PS1 cKO mouse is viable and exhibits no gross abnormalities in contrast to the pleiotropic phenotypes associated with PS1 deficiency in the embryonic brain. The carboxy-terminal fragments of the amyloid precursor protein differentially accumulate in the cerebral cortex of cKO mice, while generation of ß-amyloid peptides is reduced. Expression of Notch downstream effector genes, Hes1, Hes5, and Dll1, is unaffected in the cKO cortex. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal area CA1 synapses are normal, the PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory. These results demonstrate that inactivation of PS1 function in the adult cerebral cortex leads to reduced Aß generation and subtle cognitive deficits without affecting expression of Notch downstream genes (Yu, 2001).
The most striking feature of the disrupted APP processing is the 30-fold accumulation of the APP C-terminal fragments (CTFs) in PS1 cKO mice by the age of 6 months. Interestingly, the APP ß-CTFs (C89 and C99) accumulate differentially in the absence of PS1, with the increase in the level of C89 and C99 cleavage fragments measuring approximately 30- and 3-fold, respectively. The levels of the alpha-CTF (C83) are also elevated by as much as 30-fold. Since the CTFs represent the substrates for gamma-secretase cleavage, these results are consistent with a requirement of PS1 for gamma-secretase activity. The differential accumulation of the CTFs, particularly C89 and C99, which are cleavage products of ß-secretase, is likely due to the differences in their half lives. Alternatively, C99 could be converted to C89 by ß-secretase, resulting in much lower levels of C99 relative to C89 in the cKO mice. Furthermore, all APP CTFs are present in phosphorylated and nonphosphorylated forms in the brain of both control and cKO mice. The cytoplasmic domain of full-length APP has been shown to be phosphorylated in cultured neurons and adult rat brain by cdk5 on Thr668, which resides in the C-terminal region common to all APP CTF species. This phosphorylation event may therefore account for the observed phosphorylation of the CTFs. Although the physiological significance of APP phosphorylation is unclear, there is evidence suggesting that it may be associated with the regulation of Aß generation and neurite extension (Yu, 2001).
Although extensive data support a central pathogenic role for amyloid ß protein (Aß) in Alzheimerís disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Aß and the nature of its effects on synaptic function have not been defined in vivo. Fibrillar (but not monomeric) forms of Aß akin to those present in the amyloid plaques of Alzheimerís disease are neurotoxic in culture. However, relatively weak correlations between fibrillar plaque density and severity of dementia are found in Alzheimerís diseased brains, whereas correlations between soluble Aß levels and the extent of synaptic loss and cognitive impairment are stronger. Natural oligomers of human Aß are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Aß monomers but no amyloid fibrils markedly inhibit hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Aß species completely abrogates this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Aß monomers but not oligomers, does not prevent the inhibition of LTP. Therefore, Aß oligomers, in the absence of monomers and amyloid fibrils, disrupt synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevents oligomer formation at doses that allow appreciable monomer production, and such medium no longer disrupts LTP, indicating that synaptotoxic Aß oligomers can be targeted therapeutically (Walsh, 2002).
Adenoviral-mediated gene transfer of human amyloid precursor proteins (h-APPs) was used to evaluate the role of various h-APPs in causing neuronal cell death. PC12 cells were infected with very high efficiency: approximately 90% of the cells were cytochemically positive for beta-galactosidase activity when an adenoviral vector containing LacZ cDNA was used to infect cells. Cells infected with adenovirus containing h-APP cDNA show high-level transcription and expression of h-APP as measured by reverse transcriptase-polymerase chain reaction and Western immunoblot analyses, respectively. Intracellular and extracellular levels of h-APP were elevated approximately 17-and 24-fold in cultures infected with recombinant adenovirus containing wild-type mutant and 13- and 17-fold with V642F mutant. H-APP levels were maximal 3 days after infection. Overexpression of V642F mutant h-APP in PC12 cells and hippocampal neurons results in about a twofold increase in death compared with overexpression of wild-type h-APP. These results demonstrate the usefulness of recombinant adenoviral mediated gene transfer in cell culture studies and suggest that overexpression of a familial Alzheimer's disease mutant APP may be toxic to neuronal cells (Luo, 1999).
Clonal central nervous system neuronal cells, B103, do not synthesize detectable endogenous APP or APLP. B103 cells transfected with both wild-type (B103/APP) and mutant APP construct (B103/APP delta NL) secrete comparable amounts of soluble forms of APP (sAPP). B103/APP cells produce sAPP cleaved at amyloid beta/A4 (A beta) 16 (the alpha-secretase site). B103/APP delta NL cells produce sAPP beta cleaved at A beta 1 (the beta-secretase site). B103/APP delta NL cells develop fewer neurites than B103/APP cells in a serum-free defined medium. Neurite numbers of parent B103 cells are increased by the 50% conditioned medium (CM) from B103/APP cells but reduced by the CM from B103/APP delta NL cells. Chemically synthesized A beta, at concentration levels higher than 1 nM, reduces numbers of neurites from B103 or B103/APP delta NL cells. However, A beta at 1-100 nM does not reduce the neurite number of B103/APP cells. The protective activity against A beta's deleterious effect of reducing neurite numbers is attributable to sAPP alpha in the CM. Although sAPP alpha can block the effect of A beta, sAPP beta can not do so under the identical condition, suggesting the importance of the C-terminal 15-amino acid sequence in sAPP alpha. Nevertheless, sAPP alpha's protective activity requires the N-terminal sequence around RERMS, previously identified as the active domain of sAPP beta. The overall effect of APP mutation, which overproduces A beta and sAPP beta and underproduced sAPP alpha, is a marked decline in the neurotrophic effect of APP. It is suggested that the disruption of balance between the detrimental effect of A beta and the trophic effect of sAPP may be important in the pathogenesis of AD caused by this pathogenic APP mutation (Li, 1997).
Cholinergic deficits are one of the most consistent neuropathological landmarks in Alzheimer's disease (AD). Two transgenic mouse models, one overexpressing presenilin-1 (PS1) and a second overexpressing a mutant amyloid precursor protein (APP), and a doubly transgenic line overexpressing both genes, were examined to investigate the effect of AD-related gene overexpression and/or amyloidosis on cholinergic parameters. The size of the basal forebrain cholinergic neurons and the pattern of cholinergic synapses in the hippocampus and cerebral cortex were revealed by immunohistochemical staining for choline acetyltransferase and the vesicular acetylcholine transporter, respectively. At the time point studied (8 months), no apparent changes in either the size or density of cholinergic synapses were found in either of the two single overexpressors, relative to the nontransgenic controls. However, the doubly transgenic line showed a significant elevation in the density of cholinergic synapses in the frontal and parietal cortices. Most importantly, the double mutant, which had extensive amyloidosis, demonstrated a prominent diminution in the density of cholinergic synapses in the frontal cortex and a reduction in the size of these synapses in the frontal cortex and hippocampus. Nonetheless, no significant changes in the size of basal forebrain cholinergic neurons were observed in these three mutants. This study shows a novel role for APP and a synergistic effect of APP and PS1 that correlates with amyloid load on the reorganization of the cholinergic network in the cerebral cortex and hippocampus at the time point studied (Wong, 1999).
Amyloid precursor protein (APP) generates the beta-amyloid peptide, postulated to participate in the neurotoxicity of Alzheimer's disease. APP and APLP bind to heme oxygenase (HO), an enzyme whose product, bilirubin, is antioxidant and neuroprotective. The binding of APP inhibits HO activity, and APP with mutations linked to the familial Alzheimers disease (FAD) provides substantially greater inhibition of HO activity than wild-type APP. Cortical cultures from transgenic mice expressing Swedish mutant APP have greatly reduced bilirubin levels, establishing that mutant APP inhibits HO activity in vivo. Oxidative neurotoxicity is markedly greater in cerebral cortical cultures from APP Swedish mutant transgenic mice than wild-type cultures. These findings indicate that augmented neurotoxicity caused by APP-HO interactions may contribute to neuronal cell death in Alzheimers disease (Takahashi, 2000).
Most Down's syndrome (DS) patients develop Alzheimer's disease (AD) neuropathology. Astrocyte and neuronal cultures derived from fetal DS brain show alterations in the processing of amyloid ß precursor protein (AßPP), including increased levels of AßPP and C99, reduced levels of secreted AßPP (AßPPs) and C83, and intracellular accumulation of insoluble Aß42. This pattern of AßPP processing is recapitulated in normal astrocytes by inhibition of mitochondrial metabolism, consistent with impaired mitochondrial function in DS astrocytes. Intracellular Aß42 and reduced AßPPs are also detected in DS and AD brains. The survival of DS neurons is markedly increased by recombinant or astrocyte-produced AßPPs, suggesting that AßPPs may be a neuronal survival factor. Thus, mitochondrial dysfunction in DS may lead to intracellular deposition of Aß42, reduced levels of AßPPs, and a chronic state of increased neuronal vulnerability (Busciglio, 2002).
Impaired mitochondrial function could result from direct toxic effects of Aß or from the metabolic cost of clearing aggregated proteins through chaperones and the degradative apparatus, processes that are highly energy dependent. This model may also apply to other chronic neurodegenerative diseases characterized by intracellular protein aggregation, such as polyglutamine repeat disorders, synucleinopathies, and tauopathies. The metabolic cost of chronic protein aggregation in these diseases may lead to a state of impaired mitochondrial function and ATP depletion, giving rise to a pathological feedback loop in which protein aggregation increases and mitochondrial function is impaired further. Furthermore, impaired energy metabolism would increase neuronal vulnerability to exogenous toxic insults, such as reactive oxygen species, giving rise to a stochastic process of neuronal cell death, consistent with recent mathematical models of cell death in neurodegenerative diseases. As such, therapeutic strategies should be targeted to the prevention of protein aggregation and the restoration of normal mitochondrial function (Busciglio, 2002).
Alzheimer's disease is characterized by the deposition of senile Aβ plaques and progressive dementia. The molecular mechanisms that couple plaque deposition to neural system failure, however, are unknown. Using transgenic mouse models of AD together with multiphoton imaging, neuronal calcium was measured in individual neurites and spines in vivo using the genetically encoded calcium indicator Yellow Cameleon 3.6. Quantitative imaging revealed elevated [Ca2+]i (calcium overload) in ~20% of neurites in APP mice with cortical plaques, compared to less than 5% in wild-type mice, PS1 mutant mice, or young APP mice (animals without cortical plaques). Calcium overload depended on the existence and proximity to plaques. The downstream consequences included the loss of spinodendritic calcium compartmentalization (critical for synaptic integration) and a distortion of neuritic morphologies mediated, in part, by the phosphatase calcineurin. Together, these data demonstrate that senile plaques impair neuritic calcium homeostasis in vivo and result in the structural and functional disruption of neuronal networks (Kuchibhotla, 2008).
This study has determined at least three specific downstream functional consequences of calcium overload: spinodendritic calcium decompartmentalization, structural neuritic alterations, and CaN activation, and has also highlighted an important intermediary stage that can be targeted for therapeutic intervention -- inhibiting CaN activity leads to amelioration of the structural and functional deficits and may have behavioral implications. A critical factor that remains to be determined is the specific pathway that amyloid-β activates to induce calcium influx. The effect may be mediated by the formation of calcium-conducting pores comprised of the Aβ peptide, modulation of voltage-gated calcium channels, or an Aβ-mediated oxidative stress that results in altered calcium regulation. Nonetheless, this study shows that mutant APP processing and subsequent plaque deposition play a critical role in inducing calcium overload in these AD models and activating calcineurin-dependent neurodegenerative processes (Kuchibhotla, 2008).
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