Plasma Abeta levels do not reflect brain Abeta levels

Cerebral accumulation of amyloid beta protein (Abeta) is characteristic of Alzheimer disease (AD). Abeta can be detected in cerebrospinal fluid and in plasma. Although plasma Abeta has been proposed as a marker of risk of AD, it is unknown how plasma levels relate to neuropathologic levels. We compared plasma levels of Abeta40 and Abeta42 obtained during life with biochemical and pathologic levels in frontal and temporal neocortex in 25 individuals (17 AD, 3 control, and 5 non-AD dementia) who died a median of 1 year after blood collection. Plasma levels of Abeta40 and Abeta42 were not associated with any of the brain measures, even after adjusting for age and interval between plasma collection and death. The APOE epsilon4 allele may modify the relationship between plasma Abeta42 and formic acid-extractable Abeta42, with an inverse correlation in APOE epsilon4 carriers and a positive correlation in those lacking APOE epsilon4. We conclude that plasma levels of Abeta40 and Abeta42 are not robust correlates of histologic or biochemically assessed amyloid burdens in brain, although the influence of the APOE genotype should be further explored.     

Marked increase of β-amyloid<Subscript>(1–42)</Subscript> and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury

Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimer's disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated beta-amyloid (Abeta), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of Abeta (Abeta1-42) and two soluble forms of APP (alpha-sAPP and ss-sAPP) in ventricular cerebrospinal fluid (VCSF) and Abeta(1-42) in plasma from 28 patients in a serial samples 0-11 days after TBI. The levels of alpha-sAPP, ss-sAPP and Abeta(1-42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-Abeta(1-42) up to 1173 % from day 0-1 to day 5-6 and in VCSF-beta-sAPP up to 2033 % increase from day 0-1 to day 7-11. There was also a slight but significant increase of VCSF-beta-sAPP from day 0-1 to day 5-6 and day 7-11. By contrast, the plasma- Abeta(1-42) level is unchanged after injury. The marked increase in VCSFAbeta(1-42) implies that increased Abeta expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-Abeta(1-42) in contrast to the marked increase in VCSF-Abeta(1-42) after severe TBI, supports the suggestion that plasma Abeta(1-42) does not reflect Abeta metabolism in the central nervous system (CNS).     

Dissociation of neuropathologic findings and cognition: case report of an apolipoprotein E epsilon2/epsilon2 genotype

BACKGROUND: The apolipoprotein E (APOE) epsilon2 allele has been suggested as having a protective effect and delaying the age at onset of Alzheimer disease. OBJECTIVE: To describe a dissociation between neuropathologic findings with normal cognition in a woman with severe Alzheimer disease with the APOE epsilon2/epsilon2 genotype. DESIGN: Case report from a community-based prospective study of persons 90 years or older (The 90+ Study). PARTICIPANT: A 92-year-old woman without dementia with the APOE epsilon2/epsilon2 genotype who lived independently without significant cognitive or functional loss and was a participant in The 90+ Study. She died in December 2004, and postmortem examination of her brain was performed. INTERVENTION: Neurologic examination and a battery of neuropsychological tests were performed 6 months and 1 month before death. Neuropathologic examination included Braak and Braak staging for senile plaques and neurofibrillary tangles. RESULTS: Neuropathologic examination of the brain revealed advanced senile plaque and neurofibrillary tangle disease consistent with a high likelihood of Alzheimer disease. At clinical evaluation, the participant demonstrated no dementia and only mild cognitive deficits. CONCLUSIONS: The APOE genotype may have contributed to maintenance of cognition despite advanced neuropathologic findings of Alzheimer disease. This case suggests that the APOE epsilon2 isoform may have a protective effect against cognitive decline in Alzheimer disease that may be independent from senile plaques and neurofibrillary tangles.     

Hereditary cerebral hemorrhage with amyloidosis Dutch type (AbetaPP 693): decreased plasma amyloid-beta 42 concentration

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is a rare autosomal dominant disorder caused by an amyloid-beta precursor protein (AbetaPP) 693 mutation that clinically leads to recurrent hemorrhagic strokes and dementia. The disease is pathologically characterised by the deposition of Abeta in cerebral blood vessels and as plaques in the brain parenchyma. This study measured the Abeta40 and Abeta42 concentration in plasma of Dutch AbetaPP693 mutation carriers and controls. We found that the Abeta40 concentration was not different between AbetaPP693 mutation carriers and controls. However, the Abeta42 concentration was significantly decreased in the mutation carriers. No correlation exists between the APOE(epsilon)4 allele and the plasma of Abeta40 and Abeta42 levels in HCHWA-D patients. This finding contrasted with the increased concentrations found in Alzheimer's disease. Therefore it is suggested that the Dutch AbetaPP693 mutation located within the Abeta coding region of the AbetaPP gene has a different effect not only on clinical and pathological expression but also on Abeta processing.     

Deposition of beta-amyloid subtypes 40 and 42 differentiates dementia with Lewy bodies from Alzheimer disease.

BACKGROUND: Alterations in the metabolism of the amyloid precursor protein and the formation of beta-amyloid (Abeta) plaques are associated with neuronal death in Alzheimer disease (AD). The plaque subtype Abeta(x-42) occurs as an early event, with Abeta(x-40) plaques forming at a later stage. In dementia with Lewy bodies (DLB), an increase in the amount of cortical Abeta occurs without severe cortical neuronal losses. OBJECTIVE: To advance our understanding of the natural history of Abeta in neurodegenerative diseases. DESIGN: We evaluated the expression of Abeta(x-40) and Abeta(x-42) in DLB using monoclonal antibodies and immunohistochemical techniques in 5 brain regions. The data were compared with those elicited with normal aging and from patients with AD. SETTING AND PATIENTS: A postmortem study involving 19 patients with DLB without concurrent neuritic degeneration, 10 patients with AD, and 17 aged persons without dementia for control subjects. RESULTS: The Abeta plaques were more numerous in patients with DLB than in controls in most brain regions, although the Abeta(x-42) plaque subtype was predominant in both conditions. Overall, Abeta(x-42) plaque density was similar in patients with DLB and those with AD, but Abeta(x-40) plaques were more numerous in persons with AD than in those with DLB. The ratio of Abeta(x-40) to Abeta(x-42) plaques was significantly reduced in persons with DLB compared with patients with AD. CONCLUSIONS: The Abeta plaques were more numerous in patients with DLB than persons with normal aging, but the plaque subtypes were similar. The relative proportion of the 2 Abeta plaque subtypes in DLB is distinguishable from that in AD.     

Alzheimer beta amyloid deposition enhanced by apoE epsilon4 gene precedes neurofibrillary pathology in the frontal association cortex of nondemented senior subjects.

To clarify how Alzheimer disease pathology develops in the brains of nondemented subjects, we examined the interrelations among the amounts and morphology of Abeta deposition, neurofibrillary pathology, and apolipoprotein E (ApoE) genotype in the frontal association cortex of 101 autopsy brains from patients aged between 40 to 83. Senile plaque density correlated well with the logarithmic data of insoluble Abeta measured by enzyme immunoassay (EIA). The amounts of Abeta42-ETA increased dramatically in the late preclinical stage, whereas the AP42+ plaque density increased in the early preclinical stage. Neurofibrillary pathology appeared only in the areas with severe Abeta deposition and in subjects aged over 70. The ApoE epsilon4 allele enhanced the Abeta3 deposition in presenile subjects. Plaque-associated glial Abeta was prominent in subjects with mild to moderate Abeta deposition. The morphology of cerebral Abeta deposition changed from diffuse plaques with small amounts of Abeta in each plaque in the early preclinical stage to primitive/neuritic plaques with larger amounts of Abeta in each plaque in the late preclinical stage. Our findings suggest that the prevention of Abeta deposition in the late preclinical stage can be a rational therapeutic target, especially in elderly people with ApoE epsilon4 allele.     

Detection of amyloid plaques by radioligands for Abeta40 and Abeta42: potential imaging agents in Alzheimer's patients

Alzheimer s disease (AD) is linked to increased brain deposition of amyloid-beta (Abeta) peptides in senile plaques (SPs), and recent therapeutic efforts have focused on inhibiting the production or enhancing the clearance of Abeta in brain. However, it has not been possible to measure the burden of SPs or assess the effect of potential therapies on brain Abeta levels in patients. Toward that end, we have developed a novel radioligand, [(125)I]TZDM, which binds Abeta fibrils with high affinity, crosses the blood-brain barrier (BBB), and labels amyloid plaques in vivo. Compared to a styrylbenzene probe, [(125)I]IMSB, [(125)I]TZDM showed a 10-fold greater brain penetration and labeled plaques with higher sensitivity for in vivo imaging. However, this ligand also labels white matter, which contributes to undesirable high background regions of the brain. Interestingly, parallel to their differential binding characteristics onto fibrils composed of 40 (Abeta40)- or 42 (Abeta42)-amino-acid-long forms of Abeta peptides, these radioligands displayed differential labeling of SPs in AD brain sections under our experimental conditions. It was observed that [(125)I]IMSB labeled SPs containing Abeta40, amyloid angiopathy (AA), and neurofibrillary tangles, whereas [(125)I]TZDM detected only SPs and Abeta42-positive AA. Since increased production and deposition of Abeta42 relative to Abeta40 may be crucial for the generation of SPs, [(125)I]TZDM and related derivatives may be more attractive probes for in vivo plaque labeling. Further structural modifications of TZDM to lower the background labeling will be needed to optimize the plaque-labeling property.     

Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

OBJECTIVES: Decreased levels of Abeta1-42 are found in CSF of patients with AD. Because early stages of Creutzfeldt-Jakob disease (CJD) and AD share several clinical features, we investigated Abeta1-42 levels in CSF of these groups, inferring that this might give additional help in differentiating patients with CJD from AD patients. METHODS: We investigated 27 patients with CJD, 14 patients with AD, 19 patients with other dementias, and 20 nondemented controls (NDC) for Abeta1-42 in CSF. Twenty-four of the 27 CJD patients were neuropathologically verified. All the neuropathologically verified patients presented with a type 1 prion protein pattern. CJD patients were all homozygous for methionine at codon 129. Except in five CJD patients, no beta-amyloid plaques were seen. Additionally, APOE status was determined in patients with CJD. RESULTS: Levels of Abeta1-42 in CSF were decreased in patients with AD as well as in CJD. Levels of Abeta1-42 in CSF of patients with CJD and AD were significantly different from the other dementia and NDC groups. There was no substantial difference between the CJD and AD groups (p = 0.66). Decreased levels of Abeta1-42 did not correlate with the APOE epsilon4 load in patients with CJD. CONCLUSION: Low levels of Abeta1-42 in CSF do not exclude a diagnosis of CJD. Decreased levels of Abeta1-42 in CSF can occur without beta-amyloid plaque formation in the brain. However, the underlying mechanism of this phenomenon must be elucidated.     

Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury

Traumatic brain injury (TBI) is a risk factor for the development of Alzheimer's disease (AD). This immunohistochemical study determined the extent of AD-related changes in temporal cortex resected from individuals treated surgically for severe TBI. Antisera generated against Abeta species (total Abeta, Abeta(1-42), and Abeta(1-40)), the C-terminal of the Abeta precursor protein (APP), apolipoprotein E (apoE), and markers of neuron structure and degeneration (tau, ubiquitin, alpha-, beta-, and gamma-synuclein) were used to examine the extent of Abeta plaque deposition and neurodegenerative changes in 18 TBI subjects (ages 18-64 years). Diffuse cortical Abeta deposits were observed in one third of subjects (aged 35-62 years) as early as 2 h after injury, with only one (35-year old) individual exhibiting "mature", dense-cored plaques. Plaque-like deposits, neurons, glia, and axonal changes were also immunostained with APP and apoE antibodies. In plaque-positive cases, the only statistically significant change in cellular immunostaining was increased neuronal APP (P = 0.013). There was no significant correlation between the distribution of Abeta plaques and markers of neuronal degeneration. Diffuse tau immunostaining was localized to neuronal cell soma, axons or glial cells in a larger subset of individuals. Tau-positive, neurofibrillary tangle (NFT)-like changes were detected in only two subjects, both of more advanced age and who were without Abeta deposits. Other neurodegenerative changes, evidenced by ubiquitin- and synuclein-immunoreactive neurons, were abundant in the majority of cases. Our results demonstrate a differential distribution and course of intra- and extra-cellular AD-like changes during the acute phase following severe TBI in humans. Abeta plaques and early evidence of neuronal degenerative changes can develop rapidly after TBI, while fully developed NFTs most likely result from more chronic disease- or injury-related processes. These observations lend further support to the hypothesis that head trauma significantly increases the risk of developing pathological and clinical symptoms of AD, and provide insight into the molecular mechanisms that initiate these pathological cascades very early during severe brain injury.     

Reduction of sortilin-1 in Alzheimer hippocampus and in cytokine-stressed human brain cells

Sortilin 1 (SORL1) is a transmembrane sorting receptor that regulates the intracellular trafficking of beta-amyloid precursor protein (betaAPP). Interactions between SORL1 and betaAPP result in the decreased processing of betaAPP into toxic amyloid-beta42 (Abeta42) peptides that accumulate in Alzheimer's disease brain. Here, we report selectively decreased levels of SORL1 in limbic and occipital regions of Alzheimer brain that inversely correlate with amyloid plaque and neurofibrillary tangle density. Reduced SORL1, coupled to elevated beta-amyloid cleaving enzyme, presenilin-1 and increased Abeta42 peptide secretion, was observed after incubation of cultured human neural cells with the proinflammatory cytokine interleukin-1beta. The results suggest that SORL1 deficits may not only promote the pathogenic processing of betaAPP but may also contribute to Abeta42-mediated inflammatory signaling in stressed human brain cells.     

Brain trauma in aged transgenic mice induces regression of established abeta deposits

Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known if TBI affects the progression of AD. To address this question, we studied the neuropathological consequences of TBI in transgenic (TG) mice with a mutant human Abeta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter resulting in overexpression of mutant APP (V717F), elevated brain Abeta levels, and AD-like amyloidosis. Since brain Abeta deposits first appear in 6-month-old TG (PDAPP) mice and accumulate with age, 2-year-old PDAPP and wild-type (WT) mice were subjected to controlled cortical impact (CCI) TBI or sham treatment. At 1, 9, and 16 weeks after TBI, neuron loss, gliosis, and atrophy were most prominent near the CCI site in PDAPP and WT mice. However, there also was a remarkable regression in the Abeta amyloid plaque burden in the hippocampus ipsilateral to TBI compared to the contralateral hippocampus of the PDAPP mice by 16 weeks postinjury. Thus, these data suggest that previously accumulated Abeta plaques resulting from progressive amyloidosis in the AD brain also may be reversible.     

APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42

The epsilon4 allele of APOE is a risk factor for Alzheimer disease (AD). By analysis of a large cohort of AD patients (n = 563) and control subjects (n = 118), it is shown that the epsilon4 allele is strongly associated with reduced CSF levels of beta-amyloid (1-42) (Abeta42) in both AD (p < 10(-9)) and control (p = 0.0012) populations. As no associations of APOE variants with other indexes of AD severity were observed, this effect may reflect a fundamental involvement of ApoE in Abeta metabolism.     

Virosome-based active immunization targets soluble amyloid species rather than plaques in a transgenic mouse model of Alzheimer’s disease

Active vaccination with amyloid peptides shows promise for the treatment and prevention of Alzheimer's disease (AD). Several studies in transgenic mouse models of AD have revealed the potency of vaccination to prevent or even clear amyloid plaques from mouse brain. However, the idea that soluble oligomeric species of beta-amyloid (Abeta), rather than plaques, trigger the disease has gained momentum, and current active vaccination strategies affect the levels of total or soluble brain Abeta little or not at all. We describe an active vaccination method based on Abeta1-16 presented on the surface of virosomes, which triggered a dramatic decrease in both soluble Abeta40 (75% reduction; p=0.01) and soluble Abeta42 (62% reduction; p=0.03) in a double transgenic mouse model of AD. Whereas Abeta40 and Abeta42 levels in the insoluble fraction tended to be reduced (by 30% and 27%, respectively), the number of thioflavine-S-positive amyloid plaques was not affected. The high specific antibody responses, obtained without eliciting T-cell reactivity, demonstrate that immunostimulating reconstituted influenza virosomes are a promising antigen carrier system against the neuropathology of AD.     

BetaAPP and furin mRNA concentrates in immature senile plaques in the brain of Alzheimer patients

This study examined the possibility that in Alzheimer disease (AD) beta-amyloid precursor protein (betaAPP) mRNA is delivered to senile plaques (SPs) via dendritic processes. BetaAPP mRNA was detected in SPs by in situ hybridization, using a 1.4-kb cRNA in which both [35S]-UTP and [35S]-CTP were incorporated together. The betaAPP mRNA was compared with that of furin, a proteolytic enzyme putatively involved in betaAPP processing, and its orthologue proprotein convertase PCI served as a control. Human presenile AD cases with mostly immature SPs and AD cases generally with mature SPs were analyzed. To decrypt SPs after hybridization, brain sections were stained with thioflavin S. To establish relationships between the density of dystrophic fibers, the degree of plaque maturation, and the concentration of mRNA in SPs, the plaque maturity markers Abeta(1-42) and Abeta(1-40) peptides were co-localized with neurofilament protein 200 and compared with microtubule-associated protein 2 (MAP 2). The results suggest that immature, Abeta(1-42)- and dystrophic dendrite-containing SPs (but not mature SPs containing Abeta(1-40) and missing dystrophic dendrites) are capable of concentrating specific mRNAs. Dystrophic dendrites may thus serve as a route for the transport of specific mRNAs from the cell bodies to SPs.     

Study on the association between SOAT1 polymorphisms, Alzheimer's disease risk and the level of CSF biomarkers

BACKGROUND: In Alzheimer's disease (AD) the beta-amyloid precursor protein is excessively cleaved into Abeta(42), causing the abundant amyloid plaque loads in affected brain areas. Sterol O-acyltransferase 1 (SOAT1) has been found to regulate the production of beta-amyloid precursor protein. METHODS: We genotyped 4 SOAT1 single nucleotide polymorphism (SNP) sites (rs2247071, rs2862616, rs3753526 and rs1044925) in 410 Finnish AD cases and 455 controls and conducted a single allele and genotypic distribution comparison as well as estimating the haplotype frequencies between cases and controls and the level of biomarkers in genotype and haplotype carriers. RESULTS: The CC genotype of rs2247071 was overrepresented in the AD cases (OR = 1.38, 95% CI = 1.01-1.89, p = 0.043, Bonferroni corrected p = 0.172 with 4 tests) independent of gender, age and APOE epsilon4 allele carrier status. We did not find any significant differences between Abeta(42), tau or ptau levels in different allele, genotype or haplotype carrier cases. CONCLUSION: Our findings suggest that SOAT1 gene may possibly be only a minor risk factor in AD.     

Caspase inhibition therapy abolishes brain trauma-induced increases in Abeta peptide: implications for clinical outcome

The detrimental effects of traumatic brain injury (TBI) on brain tissue integrity involve progressive axonal damage, necrotic cell loss, and both acute and delayed apoptotic neuronal death due to activation of caspases. Post-injury accumulation of amyloid precursor protein (APP) and its toxic metabolite amyloid-beta peptide (Abeta) has been implicated in apoptosis as well as in increasing the risk for developing Alzheimer's disease (AD) after TBI. Activated caspases proteolyze APP and are associated with increased Abeta production after neuronal injury. Conversely, Abeta and related APP/Abeta fragments stimulate caspase activation, creating a potential vicious cycle of secondary injury after TBI. Blockade of caspase activation after brain injury suppresses apoptosis and improves neurological outcome, but it is not known whether such intervention also prevents increases in Abeta levels in vivo. The present study examined the effect of caspase inhibition on post-injury levels of soluble Abeta, APP, activated caspase-3, and caspase-cleaved APP in the hippocampus of nontransgenic mice expressing human Abeta, subjected to controlled cortical injury (CCI). CCI produced brain tissue damage with cell loss and elevated levels of activated caspase-3, Abeta(1-42) and Abeta(1-40), APP, and caspase-cleaved APP fragments in hippocampal neurons and axons. Post-CCI intervention with intracerebroventricular injection of 100 nM Boc-Asp(OMe)-CH(2)F (BAF, a pan-caspase inhibitor) significantly reduced caspase-3 activation and improved histological outcome, suppressed increases in Abeta and caspase-cleaved APP, but showed no significant effect on overall APP levels in the hippocampus after CCI. These data demonstrate that after TBI, caspase inhibition can suppress elevations in Abeta. The extent to which Abeta suppression contributes to improved outcome following inhibition of caspases after TBI is unclear, but such intervention may be a valuable therapeutic strategy for preventing the long-term evolution of Abeta-mediated pathology in TBI patients who are at risk for developing AD later in life.     

Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.     

Selective reductions in plasma Abeta 1-42 in healthy elderly subjects during longitudinal follow-up: a preliminary report.

OBJECTIVE: Longitudinal changes in plasma beta amyloid protein 1-42 and 1-40 (Abeta42 and Abeta40) levels and possible relationships with cognitive decline and apolipoprotein (APOE) genotype were studied in healthy elderly individuals. Methods: Authors determined cognitive level and plasma Abeta40 and Abeta42 levels twice, approximately 4 years apart, in 34 elderly subjects. Results: Analyses revealed a selective reduction in Abeta42 levels at follow-up, which were not modulated by the epsilon4 allele. Greater reductions and higher baseline plasma Abeta42 levels were associated with reductions in cognitive scores. Conclusions: Alterations in plasma Abeta42 levels may be associated with subtle cognitive decline in elderly subjects without dementia.     

Progressive worsening of adaptive functions in Down syndrome may be mediated by the complexing of soluble Abeta peptides with the alpha 7 nicotinic acetylcholine receptor: therapeutic implications

In persons with Down syndrome, soluble Abeta peptides, which result from the processing of the amyloid precursor protein, appear in the brain decades before the extracellular deposition of neuritic plaques. These soluble amyloidogenic peptides accumulate intraneuronally and can be secreted extracellularly. Their appearance has been reported in the brains of fetuses with Down syndrome. The extra gene dosage effect associated with trisomy 21 results in abnormalities of the processing of amyloid precursor protein in persons with Down syndrome. Abeta peptides, especially Abeta1-42, have been shown to form tight complexes with the alpha7 nicotinic acetylcholine receptor, interfering with transduction of the acetylcholine signal by this nicotinic receptor subtype. Furthermore, the selective binding of Abeta peptides by this nicotinic acetylcholine receptor subtype is associated with cytotoxicity. The alpha7 nicotinic acetylcholine receptor has unique electrophysiologic properties and plays a prominent role in normal psychophysiologic processes (eg, sensory inhibition) and cognition. In persons with Down syndrome there is a decrease in the ability to perform instrumental activities of daily living that worsen with aging. The progressive worsening of adaptive functions and cognition in persons with Down syndrome may be, at least in part, mediated by interference with this receptor by soluble Abeta peptides. In view of this complex formed by soluble Abeta peptides and the alpha7 nicotinic acetylcholine receptor, cholinergic interventions that have been developed for Alzheimer disease, including selective nicotinic ones, should be explored in Down syndrome. Ideally, selective cholinergic interventions would slow the progression of the worsening of adaptive function and emergence of dementia in persons with Down syndrome.     

Increased amyloid beta protein levels in children and adolescents with Down syndrome

BACKGROUND: Persons with Down syndrome (DS) (40 years and older) have neuropathological changes characteristic of Alzheimer disease (AD). Soluble forms of amyloid beta (Abeta) peptide generated from amyloid precursor protein (APP) end at C-terminal residues 40 and 42. The presence of the apolipoprotein E (ApoE) epsilon4 allele is a significant risk factor for the development of sporadic AD. Although preliminary studies have shown an association of plasma Abeta42 and ApoE epsilon4 allele in older persons with DS who have dementia, the relationship between plasma Abeta40 and Abeta42 levels and ApoE phenotypes in children with DS has not been examined. Inflammation might play a role in the growth of DS brains. Neopterin is an immune activation marker for the cell-mediated immune response. OBJECTIVE: To examine the levels of plasma Abeta40, Abeta42, and neopterin in children or adolescents with DS or controls. MATERIALS AND METHODS: Blood was collected from DS (N=35; 7+/-3.8 years old) and their siblings (N=34; 10+/-4.5). Plasma Abeta40 and Abeta42, and neopterin levels were quantitated by sandwich ELISA. RESULTS: Abeta40 and Abeta42 levels were higher in DS than controls. The ratio of Abeta42/Abeta40 was lower in DS than in controls. There were significant negative correlations between age and Abeta40 in DS and controls, and between age and Abeta42 levels in DS but not in controls. There was no association of Abeta40 or Abeta42 levels with Apo E in either group. Neopterin levels were higher in DS than controls, and the levels were not correlated with Abeta40 and Abeta42 levels in DS or controls. CONCLUSIONS: The over expression of APP gene in DS leads to increases in plasma Abeta40 and Abeta42 levels before plaque formation in DS brain. Higher neopterin concentrations in DS reflect inflammatory cell activation. Further studies are needed to determine whether DS children with lower plasma Abeta42/Abeta40 ratios are at increased risk of developing AD during aging than those with higher ratios.