Brain Expression of Presenilins in Sporadic and Early-onset, Familial Alzheimer’s Disease

Mathews, Paul M.; Cataldo, Anne M.; Kao, Benjamin H.; Rudnicki, Anna; Qin, Xi He; Yang, John; Jiang, Ying; Picciano, Melanie; Hulette, Christine M.; Lippa, Carol F.; Bird, Thomas D.; Nochlin, David; Walter, Jochen; Haass, Christian; Lévesque, Lyne; Fraser, Paul E.; Andreadis, Athena; Nixon, Ralph A.

doi:10.1007/bf03401825

Cited by 37 publications

(35 citation statements)

References 48 publications

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“…3A and B). As reported previously (14,26,40), in the AD frontal cortex PS1 is expressed prominently in the neurons of all AD brains, sporadic and familial. Importantly, immunocytochemical analysis confirmed that PS1 and AChE displayed a very similar subcellular staining in the perinuclear cytoplasm of cortical neurons (Fig.…”

Section: Resultssupporting

confidence: 79%

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Silveyra

Evin

Montenegro

et al. 2008

Molecular and Cellular Biology

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Presenilin 1 (PS1) plays a critical role in the ␥-secretase processing of the amyloid precursor protein to generate the ␤-amyloid peptide, which accumulates in plaques in the pathogenesis of Alzheimer's disease (AD). Mutations in PS1 cause early onset AD, and proteins that interact with PS1 are of major functional importance. We report here the coimmunoprecipitation of PS1 and acetylcholinesterase (AChE), an enzyme associated with amyloid plaques. Binding occurs through PS1 N-terminal fragment independent of the peripheral binding site of AChE. Subcellular colocalization of PS1 and AChE in cultured cells and coexpression patterns of PS1 and AChE in brain sections from controls and subjects with sporadic or familial AD indicated that PS1 and AChE are located in the same intracellular compartments, including the perinuclear compartments. A PS1-A246E pathogenic mutation expressed in transgenic mice leads to decreased AChE activity and alteration of AChE glycosylation and the peripheral binding site, which may reflect a shift in protein conformation and disturbed AChE maturation. In both the transgenic mice and humans, mutant PS1 impairs coimmunoprecipitation with AChE. The results indicate that PS1 can interact with AChE and influence its expression, supporting the notion of cholinergic-amyloid interrelationships.Alzheimer's disease (AD) is characterized by the presence of large numbers of amyloid plaques and neurofibrillary tangles in the brain (56). The major constituent of the amyloid plaques is the ␤-amyloid protein (A␤), a polypeptide generated by processing of a much larger amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, ␤-secretase and ␥-secretase (71). ␥-Secretase is a membrane protease complex comprising presenilin 1 (PS1) as a catalytic subunit (76). The importance of PS was first highlighted by genetic studies of AD. Families bearing mutations in the PS1 gene, or in the highly homologous presenilin 2 (PS2) gene, invariably develop an aggressive form of early-onset AD with an accelerated rate of A␤ deposition (75).The accumulation of A␤ peptide in the brain is thought to be an important step in the pathogenesis of AD, leading to a number of neurodegenerative changes (19). In particular, there is a decrease in cholinergic activity in the basal forebrain of AD patients, which affects activity of the acetylcholinesynthesizing enzyme, choline acetyltransferase, as well as the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) (13, 53). The altered expression of AChE in the AD-affected brain (AD brain) is of particular interest. Despite an overall decrease in the AD brain, the activity of AChE is increased around the amyloid plaques (42,78). This may be a direct consequence of amyloid deposition, since A␤ peptides influence AChE levels in cell cultures (25,69) and in the brains of transgenic mice that produce human A␤ (70). Conversely, AChE may play a role in A␤ fibrillogenesis (27,60). Finally, several investigations have argued for a strict interrelation b...

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Section: Resultssupporting

confidence: 79%

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Silveyra

Evin

Montenegro

et al. 2008

Molecular and Cellular Biology

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“…For immunoblotting of PS1, monoclonal antibody NT1 directed toward the N terminus (26), and MAB5232 were used. Nicastrin was immunoprecipitated and detected using polyclonal antibody N1660 (Sigma).…”

Section: Methodsmentioning

confidence: 99%

A Nine-transmembrane Domain Topology for Presenilin 1

Laudon

Hansson

Melén

et al. 2005

Journal of Biological Chemistry

167

125

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Presenilin (PS) provides the catalytic core of the ␥-secretase complex. ␥-Secretase activity leads to generation of the amyloid ␤-peptide, a key event implicated in the pathogenesis of Alzheimer disease. PS has ten hydrophobic regions, which can all theoretically form membrane-spanning domains. Various topology models have been proposed, and the prevalent view holds that PS has an eighttransmembrane (TM) domain organization; however, the precise topology has not been unequivocally determined. Previous topological studies are based on non-functional truncated variants of PS proteins fused to reporter domains, or immunocytochemical staining. In this study, we used a more subtle N-linked glycosylation scanning approach, which allowed us to assess the topology of functional PS1 molecules. Glycosylation acceptor sequences were introduced into full-length human PS1, and the results showed that the first hydrophilic loop is oriented toward the lumen of the endoplasmic reticulum, whereas the N terminus and large hydrophilic loop are in the cytosol. Although this is in accordance with most current models, our data unexpectedly revealed that the C terminus localized to the luminal side of the endoplasmic reticulum. Additional studies on the glycosylation pattern after TM domain deletions, combined with computer-based TM protein topology predictions and biotinylation assays of different PS1 mutants, led us to conclude that PS1 has nine TM domains and that the C terminus locates to the lumen/extracellular space.Most proteases operate in aqueous environments, but ␥-secretase, along with other intramembrane cleaving proteases, is unusual in the sense that it executes proteolysis in the lipid bilayer (1). ␥-Secretase is a high molecular weight protein complex composed of presenilin (PS) 2 1 or 2, nicastrin, Aph-1, and Pen-2 (2-5). Growing evidence suggests that the polytopic PS1 protein is a TM aspartyl protease and that two of its aspartate residues, Asp-257 in hydrophobic domain (HD) 6 and Asp-385 in HD 8, form the catalytic site of the ␥-secretase complex (6 -8). An endoproteolytic cleavage within HD 7 of PS1 generates an N-terminal fragment (NTF) and a C-terminal fragment (CTF) (9). The NTF/ CTF heterodimer is believed to be the biologically active form of PS. Nicastrin, Aph-1, and Pen-2 are all essential cofactors in the ␥-secretase complex, but their precise biochemical functions are not fully known. Nicastrin and Aph-1 have been proposed to form a subcomplex that can stabilize full-length PS, and the final addition of Pen-2 has been suggested to trigger PS endoproteolysis (10) and stabilize the NTF/CTF heterodimer (11). ␥-Secretase cleavage occurs within the lipid bilayer of the membrane through a mechanism referred to as "regulated intramembrane proteolysis" (12). Recently, not only APP, but a large number of other type-1 TM proteins, such as the Notch receptors, CD44 and E-cadherin, have been shown to undergo PS-dependent regulated intramembrane proteolysis (reviewed in Ref. 13). Given that target proteins of ␥-secret...

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“…Concentrations of PSEN1 have been measured in cerebrospinal fluid 51 and brains from patients with dementia and AD, with inconsistent results. [52][53][54] Phosphorylation of PSEN1 seems to increase the profibrillogenic Ab42/40 ratio and it has been found enhanced in AD brains. However, PSEN1 phosphorylation also promotes cleavage of brain insulin receptors.…”

Section: Figurementioning

confidence: 99%

Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

Luciano¹,

Barraco²,

Muraca³

et al. 2015

PEDIATRICS

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OBJECTIVE: To answer the question of whether onset of insulin resistance (IR) early in life enhances the risk of developing dementia and Alzheimer disease (AD), serum levels of 2 molecules that are likely associated with development of AD, the amyloid b-protein 42 (Ab42) and presenilin 1 (PSEN1), were estimated in 101 preschoolers and 309 adolescents of various BMI.METHODS: Participants (215 boys; 48.8%) were normal weight (n = 176; 40%), overweight (n = 135; 30.7%), and obese (n = 129; 29.3%). The HOmeostasis Model of IR (HOMA-IR), HOMA percent b-cell function (HOMA-b) and QUantitative Insulin-sensitivity Check Index (QUICKI) were calculated. RESULTS:Obese adolescents had values of Ab42 higher than overweight and normal-weight peers (190.2 6 9.16 vs 125.9 6 7.38 vs 129.5 6 7.65 pg/mL; P , .0001) as well as higher levels of PSEN1 (2.34 6 0.20 vs 1.95 6 0.20 vs 1.65 6 0.26 ng/mL; P , .0001). Concentrations of Ab42 were significantly correlated with BMI (r = 0.262; P , .0001), HOMA-IR (r = 0.261; P , .0001) and QUICKI (r = 20.220; P , .0001). PSEN1 levels were correlated with BMI (r = 0.248; P , .0001), HOMA-IR (r = 0.242; P , .0001), and QUICKI (r = 20.256; P , .0001). Western blot analysis confirmed that PSEN1 assays measured the full-length protein.CONCLUSION: Obese adolescents with IR present higher levels of circulating molecules that might be associated with increased risk of developing later in elderly cognitive impairment, dementia, and AD. WHAT'S KNOWN ON THIS SUBJECT:Insulin resistance plays a role in obesity. Recently it has been associated with increased risk of AD. Ab42 and PSEN1 are molecules associated with increased risk of later AD. Patients affected by AD show elevated levels of plasma Ab42.WHAT THIS STUDY ADDS: Levels of Ab42 and PSEN1 are significantly elevated in obese adolescents and correlated with the degree of both adiposity and systemic insulin resistance. Dr Manco conceptualized and designed the study, performed assays, analyzed data and interpreted results, contributed to the discussion, and critically revised the manuscript; Ms Luciano and Ms Barraco conceptualized and designed the study, performed assays, analyzed data and interpreted results, and drafted the manuscript; Drs Muraca, Ottino, Sforza, Rustico, and Morino and Ms Spreghini enrolled patients, collected growth data, and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This condition has been termed as "brain insulin resistance" and seems to be a constant trait that precedes clinical symptoms of dementia and AD even for decades. Researchers refer to AD also as "type 3 diabetes" by virtue of the analogous brain glucose hypometabolism that characterizes both conditions and the high rate of their co-occurrence. 1,4,5 Patients with T2D exhibit an increased risk of developing cognitive impairment and dementia and, vice versa, impaired fasting glucose and diabetes are highly prevalent among patients...

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Brain Expression of Presenilins in Sporadic and Early-onset, Familial Alzheimer’s Disease

Cited by 37 publications

References 48 publications

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

A Nine-transmembrane Domain Topology for Presenilin 1

Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

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