Piet Eikelenboom

Astrocytic A beta 1-42 Uptake Is Determined by A beta-Aggregation State and the Presence of Amyloid-Associated Proteins

Intracerebral accumulation of amyloid‐β (Aβ) leading to Aβ plaque formation, is the main hallmark of Alzheimers disease and might be caused by defective Aβ‐clearance. We previously found primary human astrocytes and microglia able to bind and ingest Aβ1‐42 in vitro, which appeared to be limited by Aβ1‐42 fibril formation. We now confirm that astrocytic Aβ‐uptake depends on size and/or composition of Aβ‐aggregates as astrocytes preferably take up oligomeric Aβ over fibrillar Aβ. Upon exposure to either fluorescence‐labelled Aβ1‐42 oligomers (Aβoligo) or fibrils (Aβfib), a larger (3.7 times more) proportion of astrocytes ingested oligomers compared to fibrils, as determined by flow cytometry. Aβ‐internalization was verified using confocal microscopy and live‐cell imaging. Neither uptake of Aβoligo nor Aβfib, triggered proinflammatory activation of the astrocytes, as judged by quantification of interleukin‐6 and monocyte‐chemoattractant protein‐1 release. Amyloid‐associated proteins, including α1‐antichymotrypsin (ACT), serum amyloid P component (SAP), C1q and apolipoproteins E (ApoE) and J (ApoJ) were earlier found to influence Aβ‐aggregation. Here, astrocytic uptake of Aβfib increased when added to the cells in combination with SAP and C1q (SAP/C1q), but was unchanged in the presence of ApoE, ApoJ and ACT. Interestingly, ApoJ and ApoE dramatically reduced the number of Aβoligo‐positive astrocytes, whereas SAP/C1q slightly reduced Aβoligo uptake. Thus, amyloid‐associated proteins, especially ApoJ and ApoE, can alter Aβ‐uptake in vitro and hence may influence Aβ clearance and plaque formation in vivo.

Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology.

Alzheimers disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.

Neuronal COX-2 expression and phosphorylation of pRb precede p38 MAPK activation and neurofibrillary changes in AD temporal cortex

In Alzheimers disease (AD) brain, increased levels of cyclooxygenase-2 (COX-2), cell cycle markers, and p38 MAP kinase (MAPK) can be detected in neuronal cells. Besides mediating COX-2 expression, p38 MAPK is suggested to mediate cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In this study, we show that neuronal immunoreactivity for phosphorylated p38 MAPK does not correlate with COX-2 or phosphorylated pRb (ppRb) in control and AD temporal cortex. Immunoreactivity for activated p38 MAPK co-localizes with AT8 immunoreactivity and increases with the occurrence of neurofibrillary tangles and plaques. On the other hand, COX-2 immunoreactivity co-localizes and correlates with ppRb immunoreactivity in pyramidal neurons. COX-2 and ppRb do not co-localize with AT8 and decrease with increasing pathology. These results suggest that p38 MAPK does not mediate COX-2 expression and pRb inactivation, which are involved in cellular changes in pyramidal neurons early in AD pathogenesis.

Schizophrenia spectrum disorders in later life: prevalence and distribution of age at onset and sex in a Dutch catchment area

OBJECTIVESnThe prevalence of schizophrenia in later life is affected by both outflow of early onset patients, due to recovery and excess mortality, and inflow of patients with a later age at onset, making it likely that characteristics of older patients differ markedly from younger patients. We assessed the prevalence of schizophrenia and spectrum disorders and their distribution according to age at onset and sex in an elderly population.nnnDESIGNnCase register study.nnnSETTING AND PARTICIPANTSnAll patients age 60 years and older, in contact with the Mental Health Organization in a psychiatric catchment area in Amsterdam (the Netherlands), diagnosed with schizophrenia, schizoaffective disorder, or delusional disorder.nnnMEASUREMENTSnOne-year prevalence estimates, including rates according to age group, age at onset, and sex. In addition, we determined the effect of using different criteria for age at onset.nnnRESULTSnThe one-year prevalence of all disorders was 0.71%, subdivided in 0.55% for schizophrenia, 0.14% for schizoaffective disorder, and 0.03% for delusional disorder. The one-year prevalence of early-onset schizophrenia was 0.35%, of late-onset schizophrenia 0.14%, and of very-late-onset schizophrenia-like psychosis 0.05%. Variation of onset criterion affected the proportion of early-onset versus late-onset schizophrenia patients stronger in women than in men. Women outnumbered men markedly in the prevalence estimates for most diagnostic subgroups, including early-onset schizophrenia.nnnCONCLUSIONSnWe found the prevalence of schizophrenia among older persons to be well within the range reported for younger populations. The considerable proportion with a later age at onset and the strong female preponderance are distinguishing characteristics of older patients with clinical implications.

Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro.

Defective clearance of the amyloid‐β peptide (Aβ) from the brain is considered a strong promoter in Alzheimers disease (AD) pathogenesis. Astrocytes and microglia are important mediators of Aβ clearance and Aβ aggregation state and the presence of amyloid associated proteins (AAPs), such as Apolipoproteins E and J (ApoE and ApoJ), may influence Aβ clearance by these cells. Here we set out to investigate whether astrocytes and microglia differ in uptake efficiency of Aβ oligomers (Aβoligo) and Aβ fibrils (Aβfib), and whether the Aβ aggregation state and/or presence of AAPs affect Aβ uptake in these cells in vitro. Adult human primary microglia and astrocytes, isolated from short delay post‐mortem brain tissue, were exposed to either Aβoligo or Aβfib alone or combined with a panel of certain AAPs whereafter Aβ‐positive cells were quantified using flow cytometry. Upon exposure to Aβ combined with ApoE, ApoJ, α1‐antichymotrypsin (ACT) and a combination of serum amyloid P and complement C1q (SAP‐C1q), a clear reduction in astrocytic but not microglial Aβoligo uptake, was observed. In contrast, Aβfib uptake was strongly reduced in the presence of AAPs in microglia, but not in astrocytes. These data provide the first evidence of distinct roles of microglia and astrocytes in Aβ clearance. More importantly we show that Aβ clearance by glial cells is negatively affected by AAPs like ApoE and ApoJ. Thus, targeting the association of Aβ with AAPs, such as ApoE and ApoJ, could serve as a therapeutic strategy to increase Aβ clearance by glial cells. GLIA 2014;62:493–503

Activated microglial cells and complement factors are unrelated to cortical Lewy bodies.

Abstract Inflammatory mechanisms have been demonstrated in Alzheimer’s disease (AD) but their presence in other neurodegenerative disorders is not well documented. Complement factors and activated microglia have been reported in the substantia nigra of Parkinson’s disease (PD). In the present study we investigated the cingulate gyrus of 25 autopsied patients with clinically and neuropathologically well-documented PD, with or without dementia, for the presence of (activated) microglial cells and their relation with Lewy body (LB)-bearing neurons. In addition, we studied the presence of complement factors in LBs. Of the 25 patient, 15 were clinically demented, fulfilling criteria for dementia with LBs (DLB); 7 also fulfilled CERAD morphological criteria for probable or definite Alzheimer type of dementia. Microglia clustering was seen around congophilic plaques with or without tau pathology. Microglial cells were not associated with LB-bearing neurons or noncongophilic plaques. The cortex of DLB patients without AD plaques did not show more microglial cells than the cortex of non-demented controls. The number of microglia was the lowest in young control patients who died immediately after trauma. Complement factor C3d was occasionally seen in diffusely ubiquinated neurons but late complement factors were not detected in these neurons. Double staining for complement and α-synuclein was negative, suggesting the absence of complement in LBs. In contrast, AD plaques in the same sections showed complement factors C3c, C3d, C1q and C5–9. In conclusion, we have found no evidence that inflammatory mechanism are involved in LB formation in cerebral cortex.

Subjective quality of life and its determinants in a catchment area based population of elderly schizophrenia patients

BACKGROUNDnSubjective quality of life (SQOL) is an established outcome measure in schizophrenia. In spite of the substantial proportion of elderly in the total schizophrenia population, evaluation of their SQOL and its determinants has been scarce and findings from epidemiological samples are lacking.nnnMETHODSnWe assessed SQOL in elderly Dutch patients with schizophrenia or schizoaffective disorder (n=107; mean age 68 years), treated within a psychiatric catchment area. Demographic, clinical and social variables were evaluated for their impact on SQOL.nnnRESULTSnThe mean SQOL score was 4.83, moderately surpassing the midpoint of the SQOL scale. Nearly half of all patients (47.7%) reported an overall favorable SQOL. Of the total variance in SQOL, clinical variables explained 50%, and social variables explained 16%, while demographic factors did not contribute. In multivariable analysis, less self-reported depressive symptoms, worse global neurocognition, and higher observer-based level of social functioning significantly predicted a higher SQOL, explaining 53% of the total variance.nnnCONCLUSIONnThe relatively high level of SQOL in this epidemiological sample of elderly patients is in line with what has been reported for both older and younger schizophrenia populations. Depressive symptoms are a robust predictor of SQOL in late life schizophrenia, clearly outweighing psychotic symptoms. This finding has major clinical relevance, as depression is amenable to therapeutic intervention.

Cognitive impairment in late life schizophrenia and bipolar I disorder

Evidence in younger populations suggests quantitative but not categorical differences in cognitive impairments between schizophrenia and bipolar disorder. It is uncertain whether a similar distinction applies to patients in later life.

Symptomatic remission and associated factors in a catchment area based population of older patients with schizophrenia

BACKGROUNDnSymptomatic remission and its associated factors have been evaluated in several studies of younger schizophrenic patients. Although the number of older individuals with schizophrenia is rapidly growing, evaluations of remission in elderly patients are scarce and limited to samples of convenience, questioning their generalizability to unselected patient populations.nnnMETHODSnWe assessed the rate of symptomatic remission in a cohort of older Dutch schizophrenic patients within a psychiatric catchment area. In addition, we examined the association of symptomatic remission with measures of mental health treatment, social functioning, cognition, mood, and quality of life.nnnRESULTSnWith a rate of 29.4%, symptomatic remission in this catchment area based cohort of older schizophrenic patients (mean age 68 years) was markedly lower than the rates reported for convenience samples. Remission was more frequent in schizoaffective patients, compared to patients with schizophrenia. Remitted patients were more adherent to psychiatric services and scored higher on measures of social functioning. No association with symptomatic remission could be demonstrated for cognition, mood, and quality of life.nnnCONCLUSIONnThe modest rate of symptomatic remission in this treated sample of elderly schizophrenic patients questions the notion that old age is associated with high levels of symptomatic remission. The concurrent validity of the remission concept in elderly patients merits further investigation, given the limited number of demonstrated associations.

Insulin-like growth factor-1 and risk of late-onset Alzheimer's disease: findings from a family study

Insulin-like growth factor-1 (IGF-1), part of an evolutionary conserved signaling pathway in both mammalian and non-mammalian species, is inferred in neurodegenerative disorders including Alzheimers disease (AD). A murine model for AD shows that reduced IGF-1 signaling prevents AD-like characteristics. However, variation in serum levels of IGF-1 and risk of AD in humans has yet to be determined. We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. The offspring under study carry an increased risk of AD but do not yet experience cognitive impairment. A total of 206 offspring from 92 families with a parental history of AD were compared with 200 offspring from 97 families without a parental history of AD. Apolipoprotein-E (APOE) genotypes and serum IGF-1 levels were compared in subjects with and without a parental history of AD using linear regression, adjusted for APOE genotype and other possible demographic and clinical confounders. Offspring with a parental history of AD were more likely to be an APOE ε4 allele carrier (46.5% vs. 21%, p = 0.001) than were offspring without such a parental history. Offspring with a parental history of AD had higher IGF-1 levels than subjects without such a history, in both unadjusted and adjusted analyses (18.3 mmol/L vs. 16.7 mmol/L, p = 0.001). In conclusion, higher serum IGF-1 levels in middle age are associated with risk of AD disease in older age, independent of APOE genotype.