Longitudinal observation on CSF A?42 levels in young to middle-aged amyloid precursor protein/presenilin-1 doubly transgenic mice

Liu, Li; Herukka, Sanna‐Kaisa; Minkeviciene, Rimante; Groen, Thomas van; Tanila, Heikki

doi:10.1016/j.nbd.2004.08.005

Cited by 35 publications

(40 citation statements)

References 33 publications

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“…CSF levels would remain within normal values during very early phases of the disease to approach pathological values in the last decade of the preclinical stage as had also been previously demonstrated both in sporadic and FAD cases [4,5,10,11] . All these data are in accordance with findings in double APP / PSEN1 transgenic mice in which levels of A ␤ 1-42 initially reflect the rate of A ␤ 1-42 production, but after reaching a critical concentration stay in equilibrium, until plaque formation leads to decreased A ␤ 1-42 [16] . It is also of interest to underline that A ␤ 1-42 levels were not correlated with age or adjusted age in NC in this study, consistent with previous studies in cognitive preserved subjects [22] .…”

Section: Discussionsupporting

confidence: 91%

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Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

et al. 2011

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Background/Aims: Familial Alzheimer’s disease allows studies in the preclinical phases of the disease. We studied cerebrospinal fluid (CSF) amyloid β1–42 (Aβ1–42), total tau (t-tau) and phospho-tau181 (p-tau) levels in PSEN1 families and correlated the results with the genetic status, age and clinical stage. Methods: Thirteen subjects from 3 families with 2 PSEN1 mutations (L286P, M139T) were recruited from the genetic counseling program for familial dementia. Eight mutation carriers (MC) and 5 noncarriers (NC) underwent clinical and cognitive evaluations. CSF concentrations were obtained by ELISA methodology. Results: Symptomatic MC presented reduced CSF Aβ1–42 (mean = 175 pg/ml) and elevated t-tau (mean = 635 pg/ml) compared to controls, but not asymptomatic MC (mean = 684 and 255 pg/ml, respectively) at a median of –12.8 years from the predicted disease onset (adjusted age). Aβ1–42 levels presented an inverse correlation with the adjusted age (r = –1, p < 0. 01) in asymptomatic MC, but not in symptomatic MC or NC. t-tau presented a trend towards a negative correlation with Mini Mental State Examination (MMSE; r = –0.949, p = 0.051) in symptomatic MC but not in asymptomatic MC. In the whole group of MC, t-tau presented a significant positive correlation with Clinical Dementia Rating sum of boxes (r = 0.913, p = 0.002) and a negative correlation with MMSE (r = –0.946, p < 0.001). Conclusions: CSF Aβ1–42 levels correlate with time to disease onset in asymptomatic MC to reach floor levels when symptoms appear. CSF t-tau levels become elevated in symptomatic MC and correlate with clinical severity. These findings may suggest that the changes in Aβ1–42 precede t-tau elevation in PSEN1 MC.

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Section: Discussionsupporting

confidence: 91%

“…Individually, all SMC had low A ␤ 1-42 ( table 1 ), clearly below threshold levels [16] . As a group, SMC had significantly lower A ␤ 1-42 levels (mean = 175 pg/ml) than NC (mean = 675 pg/ml; p = 0.016) or AMC (mean 684 pg/ ml; p = 0.029; table 2 ).…”

Section: Amyloid ␤ 1-42mentioning

confidence: 93%

Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

et al. 2011

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“…Our finding of amyloid plaques in 10-to 14-month-old mice corresponds to an earlier report (Garcia-Alloza et al, 2006), and the high A␤ 1-42 peptide levels observed in this previous study (approximately 1.0 nmol/g wet tissue, corresponding to 4.5 g/g) were confirmed in our measurements (6.6 g/g wet weight). In another study, a slightly lower value (2.2 g/g) was reported for hippocampal tissue of these animals (Liu et al, 2004). However, it should be noted that most of this A␤ 1-42 is "insoluble" peptide that was solubilized from tissue by guanidine (see under Materials and Methods).…”

Section: Discussionmentioning

confidence: 75%

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain

Hartmann¹,

Kiewert²,

Klein³

2009

J Pharmacol Exp Ther

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Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, synaptic loss and central cholinergic dysfunction, dysfunction of energy metabolism, and dementia; however, the interactions between these hallmarks remain poorly defined. We studied a well characterized mouse model of amyloid deposition, the doubly transgenic APP SWE ϫPSEN1dE9 mouse. At 10 to 14 months of age, these mice had high levels of amyloid peptides (6.6 g/g wet weight) and widespread amyloid plaques. Extracellular levels of acetylcholine (ACh) were determined by microdialysis in the hippocampus and were comparable with nontransgenic mice from the same colony. In the open field, both mouse strains responded with a 3-fold increase of hippocampal ACh release. Exploratory behavior of the transgenic mice appeared normal. Infusion of scopolamine evoked 5-to 6-fold increases of ACh levels in both mouse strains. High-affinity choline uptake and cholinesterase activities were identical in both mouse lines. Extracellular levels of glucose and glycerol were similar in control and transgenic mice, whereas lactate levels were slightly (p ϭ 0.06) and glutamate levels significantly (p ϭ 0.02) lower in transgenic mice. Exploration caused increases of glucose and lactate, whereas infusion of scopolamine (1 M) increased glucose but not lactate. Glutamate levels were increased by scopolamine, whereas glycerol remained constant under all the conditions. We conclude that amyloid peptide production and plaque deposition causes minor changes in cholinergic function and energy metabolites in transgenic mice in vivo. Amyloid peptide formation and/or deposition may not be sufficient for long-term cholinergic or metabolic dysfunction.Alzheimer's disease (AD) is the most frequent type of dementia in humans and is characterized by cognitive dysfunction and early memory loss (Blennow et al., 2006;Burns and Iliffe, 2009). AD brains display amyloid plaques and neurofibrillary tangles, as well as neuronal degeneration and generalized atrophy. Cholinergic fibers originating in the basal forebrain and innervating hippocampus and cortex seem to degenerate relatively early in the disease, although the clinical evidence is somewhat controversial (Mesulam, 2006;Schliebs and Arendt, 2006). In later stages of the disease, cholinergic dysfunction correlates well with dementia, and current therapies of AD use inhibitors of acetylcholinesterase (AChE) to enhance cholinergic transmission in the brain. Although treatment of AD with AChE inhibitors as a monotherapy has only limited effects, successful treatment of dementia will probably not be possible without correcting the cholinergic deficit. Thus, the understanding of the cholinergic dysfunction and its development remains highly relevant for drug treatment of AD.In clinical studies, AD can be distinguished in early onset disease (familial AD) and late-onset, sporadic disease (Blennow et al., 2006;Burns and Iliffe, 2009). The rare familial AD cases have mutations in genes coding for...

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“…Cerebral spinal fluid (CSF) was collected according to a published method (Liu et al ., 2004) with minor modifications as previously described (Wang et al ., 2015; Yu et al ., 2015). …”

Section: Methodsmentioning

confidence: 99%

Prostaglandin I ₂ upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

et al. 2016

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SummaryCyclooxygenase‐2 (COX‐2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX‐2 metabolic product, prostaglandin (PG) I2, in the pathogenesis of AD remains unknown. Using human‐ and mouse‐derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx‐defective (APH)‐1α and pharynx‐defective‐1β induction. In particular, we found that PGI 2 production increased during the course of AD development. Then, PGI 2 accumulation in neuronal cells activates PKA/CREB and JNK/c‐Jun signaling pathways by phosphorylation, which results in APH‐1α/1β expression. As PGI 2 is an important metabolic by‐product of COX‐2, its suppression by NS398 treatment decreases the expression of APH‐1α/1β in neuronal cells and APP/PS1 mice. More importantly, β‐amyloid protein (Aβ) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH‐1α/1β, which was blocked by NS398 incubation. Finally, the induction of APH‐1α/1β was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI 2‐induced AD progression but also are instrumental for improving clinical therapies to combat AD.

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Longitudinal observation on CSF A?42 levels in young to middle-aged amyloid precursor protein/presenilin-1 doubly transgenic mice

Cited by 35 publications

References 33 publications

Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain

Prostaglandin I ₂ upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

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Longitudinal observation on CSF A?42 levels in young to middle-aged amyloid precursor protein/presenilin-1 doubly transgenic mice

Cited by 35 publications

References 33 publications

Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APPSWE×PSEN1dE9 Mouse Brain

Prostaglandin I 2 upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

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Product

Resources

About

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain

Prostaglandin I ₂ upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice