Alzheimer Disease Developments – Spring 2015
Larry H. Bernstein, MD, FCAP, Curator
LPBI
Cognitive Stimulation Modulates Platelet Total Phospholipases A2 Activity in Subjects with Mild Cognitive Impairment
Article type: Short Communication
Authors: Balietti, Martaa; 1; * | Giuli, Cinziab; 1 | Fattoretti, Patriziaa | Fabbietti, Paoloc | Postacchini, Demetriob | Conti, Fiorenzoa; d
Journal: Journal of Alzheimer’s Disease, 2016; 50(4):957-962, http://content.iospress.com/articles/journal-of-alzheimers-disease/jad150714http://dx.doi.org:/10.3233/JAD-150714
Supplementary Table 1
We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.
Phospholipases A2 (PLA2) form a superfamily of enzymes that catalyze production of lyso-phospholipids and free fatty acids by the hydrolysis of phospholipids sn-2 ester bond. They play a pivotal role in many physiological processes, including membrane remodelingand cell signaling [1, 2], and are involved in neurodegenerative disorders [3, 4].
PLA2 modulation is a potential therapeutic target [5, 6]; in this context, cognitive stimulation (CS) is particularly promising, not only because in animal models it has effective regulating properties [7], but also because it is non-invasive, has no side effects, and presents no contraindications.
To date, only one study has been performed in humans: in a little cohort of healthy elderly subjects, a memory training intervention was proved to modulate platelet PLA2 activity [8]. The use of platelet PLA2 as peripheral biomarker of the neuronal enzyme is convincing in light of the recent finding that total PLA2 (tPLA2) activity in thrombocytes may mirror thetotal activity in the brain [9]. Moreover, platelets are widely considered “circulating neurons” because of the similarities existing between the two cells in terms of enzymes, receptors, and metabolic products [10, 11].
On these grounds, we evaluated the effects of CS on platelet tPLA2 activity in a cohort of subjects with mild cognitive impairment (MCI).
The present study showed that in subjects with MCI, platelet tPLA2 activity correlates with patients’ cognitive conditions, and that CS acts selectively on the enzyme, i.e., it modulates the parameter only in individuals with deregulated values in comparison to the healthy elderly.
Based on the MMSE score, it was possible to subdivide at baseline the MCI cohort into two subgroups: patients with more evident cognitive impairment (MMSE score <26) and significantly higher tPLA2 activity, and individuals cognitively more preserved (MMSE score ≥26), who had tPLA2 activity similar to the healthy elderly. The finding that the increase of tPLA2 activity and the severity of the global cognitive status impairment are significantly linked suggests a possible role of tPLA2 in MCI progression. PLA2 activity alterations may lead to the synthesis of excessive proinflammatory mediators and peroxidative products [19], and inflammation and oxidative stress may contribute to the pathogenesis of Alzheimer’s disease (AD) [20, 21], of which MCI could be a prodromal condition. It is therefore conceivable that the more deregulated tPLA2 is, the more harmful molecules might be released, and the more severe the pathological consequences might become. The finding that in patients affected by AD tPLA2 activity is significantly higher than in healthy controls [22, 23] as well as in MCI subjects [23] is in line with this hypothesis.
As far as the therapeutic potentialities of CS are concerned, the protocol not only exerted positive effects on several cognitive outcomes, but also counteracted the peripheral enzymatic deregulation. Indeed, CS improved parameters linked to memory, attention, and verbal, confirming the results of others [24]. It is worth noting that CS acts on tPLA2 activity in a “dysfunction-dependent” mode: in subjects with an initial enzymatic activity higher than in the healthy elderly (Subgroup 1), CS reduced the value; in subjects with an initial enzymatic activity similar to the healthy elderly (Subgroup 2) CS did not induce any significant change. Thus, CS seems to have homeostatic properties on tPLA2 activity. This result may seem in contradictionwith the observation that in the healthy elderly CS induces platelet tPLA2 increase [8]. Actually, it is conceivable that, in absence of pathology, increased activity produced by the training improves cell functioning while in MCI, where the increased values might be linked to inflammation and oxidative stress, the protocol acts in the opposite way. Indeed, recent evidence supports the use of specific PLA2 inhibitors as preventive/therapeutic agents for inflammatory disorders [25], and several studies showed that environmental enrichment exert anti-inflammatory and neuromodulatory effects [26]. Thus, in MCI and AD, where the involvement of neuroinflammation is well established [27, 28], CS may produce a down regulation effect in the central nervous system, which might influence also circulation blood components.
In conclusion, this study suggests that platelet tPLA2 activity may be useful as peripheral biomarker to differentiate MCI patients at different pathological stages, and sustains the use of CS as non-pharmacological therapeutic strategy.
JNK: A Putative Link Between Insulin Signaling and VGLUT1 in Alzheimer’s Disease
Normal Amplitude of Electroretinography and Visual Evoked Potential Responses in AβPP/PS1 Mice
Authors: Leinonen, Henri* | Lipponen, Arto1 | Gurevicius, Kestutis | Tanila, Heikki
Journal: Journal of Alzheimer’s Disease, 2016; 51(1):21-26 http://dx.doi.org:/10.3233/JAD-150798
Alzheimer’s disease has been shown to affect vision in human patients and animal models. This may pose the risk of bias in behavior studies and therefore requires comprehensive investigation. We recorded electroretinography (ERG) under isoflurane anesthesia and visual evoked potentials (VEP) in awake amyloid expressing AβPPswe/PS1dE9 (AβPP/PS1) and wild-type littermate mice at a symptomatic age. The VEPs in response to patterned stimuli were normal in AβPP/PS1 mice. They also showed normal ERG amplitude but slightly shortened ERG latency in dark-adapted conditions. Our results indicate subtle changes in visual processing in aged male AβPP/PS1 mice specifically at a retinal level.
Brain Metabolism Correlates of The Free and Cued Selective Reminding Test in Mild Cognitive Impairment
Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology
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Stern, Robert A. | Tripodis, Yorghos | Baugh, Christine M. | Fritts, Nathan G. | Martin, Brett M. | Chaisson, Christine | Cantu, Robert C. | Joyce, James A. | Shah, Sahil | Ikezu, Tsuneya | Zhang, Jing | Gercel-Taylor, Cicek | Taylor, Douglas D
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Predictive Value of Cerebrospinal Fluid Visinin-Like Protein-1 Levels for Alzheimer’s Disease Early Detection and Differential Diagnosis in Patients with Mild Cognitive Impairment
Babić Leko, Mirjana | Borovečki, Fran | Dejanović, Nenad | Hof, Patrick R. | Šimić, Goran
Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study
Chatterjee, Pratishtha | Lim, Wei L.F. | Shui, Guanghou | Gupta, Veer B. | James, Ian | …… | Wenk, Marcus R. | Bateman, Randall J. | Morris, John C. | Martins, Ralph N.
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A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline/ Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, et al. / Nature. 2012 Aug 2; 488(7409):96-9. PMID: 22801501.
Propagation of tau pathology in a model of early Alzheimer’s disease / de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, et al. / Neuron. 2012 Feb 23; 73(4):685-97. PMID: 22365544.
Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years/ Braak H, Thal DR, Ghebremedhin E, Del Tredici K / J Neuropathol Exp Neurol. 2011 Nov; 70(11):960-9. PMID: 22002422.
Neuroinflammation in Alzheimer’s disease and mild cognitive impairment: a field in its infancy / McGeer EG, McGeer PL / J Alzheimers Dis. 2010; 19(1):355-61. PMID: 20061650.
Metallothioneins in Prion- and Amyloid-Related Diseases
Do Microglia Default on Network Maintenance in Alzheimer’s Disease?
Article type: Research Article
Authors: Southam, Katherine A.1; * | Vincent, Adele J.1 | Small, David H.
Journal: Journal of Alzheimer’s Disease, 2016; 51(3):657-669 http://dx.doi.org:/10.3233/JAD-151075
Although the cause of Alzheimer’s disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain’s immune cells. They play an important role in maintaining the brain’s extracellular environment, including clearance of aggregated proteins such as amyloid-β (Aβ). Recent studies suggest that microglia play a more active role in the brain than initially considered. Specifically, microglia provide trophic support to neurons and also regulate synapses. Microglial regulation of neuronal activity may have important consequences for AD. In this article we review the function of microglia in AD and examine the possible relationship between microglial dysfunction and network abnormalities, which occur very early in disease pathogenesis.
Alzheimer’s disease (AD) is a progressive, neurodegenerative disease that primarily affects the regions of the brain that are associated with high functioning. AD is characterized by progressive dementia that begins with mood changes, memory loss, and reduced cognition [1]. The primary pathogenic process in AD is the accumulation of amyloid-β protein (Aβ) [1–3]. Aβ aggregates into extracellular amyloid plaques that are a hallmark pathological feature of the disease. Aβ is cleaved from the larger amyloid-β protein precursor (AβPP) [4–6]. However, it remains unclear why Aβ, a protein fragment normally only present in small amounts within the brain, is able to accumulate in the AD brain and cause toxicity. In a small percentage (5%) of AD sufferers, the cause of the disease is genetic. Inherited mutations within the AβPP gene itself appear to predispose the protein to Aβ production [7]. Mutations within the presenilin 1 and 2 genes, encoding proteins that form part of the secretase complex that cleaves the Aβ peptide from AβPP, also result in inherited AD due to accumulations of Aβ [8–11].
The cause of AD is largely unknown for the remaining 95% of cases of sporadic AD, which typically develops a decade or two later than familial AD [12]. However, the degenerative processes are nearly identical between the two forms of the disease. Therefore, it is reasonable to assume that the underlying disease process is the same between the two forms of the disease. Genetic studies have identified a number of genetic risk factors for AD. An early discovery was that allelic variants of apolipoprotein E (ApoE) carry inherently different risks of AD [13–15]. In particular, the ɛ4 allele carries a high risk of AD, with risk of disease occurring in a dose-dependent manner based onzygosity. The ApoE ɛ4 allele is associated with increased Aβ aggregation, reduced lipid transport, and reduced receptor-mediated Aβ clearance [16]. Interestingly, ApoE is predominantly expressed by non-neuronal cells— astrocytes and microglia, rather than by neurons [17]. These findings suggested that although clinical AD manifests from neuronal degeneration, other cells of the central nervous system (CNS) may be intimately involved in pathogenesis or disease progression.
More recently, genome-wide association studies (GWAS) have been used to identify a large number of risk genes for AD. In 2013, a mutation in the triggering receptor expressed on myeloid cells 2 (TREM2) was identified [18, 19]. TREM2 is almost exclusively expressed by immune cells within the brain, and mutations to TREM2 are associated with decreased phagocytosis and an increased pro-inflammatory reactive phenotype. Individuals heterozygous for TREM2 mutations have a high risk of developing AD, however the mutation is rare [18, 19]. Additional AD risk factor genes that have been identified include genes associated with lipid processing, endocytosis, and the immune response, which have recently been covered in excellent reviews [20, 21]. The common unifying feature of these immune-associated mutations is that they are proposed to interfere with microglial function, in particular, the efficiency of phagocytosis [20]. Specifically, mutations to complement receptor 1 (CR1) and cluster of differentiation 33 (CD33) can result in reduced activity of the complement system and reduced phagocytosis [22, 23]. Phosphatidylinositol binding clathrin assembly protein (PICALM) and bridging integrator 1 (BIN1) mutations affect clathrin-mediated endocytosis [24, 25] and SORL1 mutations reduce intracellular trafficking of AβPP [26]. The function of some of these proteins in relation to phagocytosis is discussed later in this review. The identification of such a wide array of risk genes associated with reduced immune cell function now leads us to believe that abnormal functioning of immune cells may play a more important role in the early stages of disease than previously considered.
MICROGLIA
Microglia are the immune cells of the CNS and account for approximately 10% of the CNS cellpopulation, with regional variation in density [27, 28]. During embryonic development, microglia originate from yolk sac progenitor cells that migrate into the developing CNS during early embryogenesis [29,30].Following construction of the blood-brain barrier (BBB), microglia are renewed by local turnover [31]. In the healthy brain, microglia actively support neurons through the release of insulin-like growth factor 1, nerve growth factor, ciliary neurotrophic factor, and brain-derived neurotrophic factor (BDNF) [32–34]. Microglia also provide indirect support to neurons by clearance of debris to maintain the extracellular environment, and phagocytosis of apoptotic cells to facilitate neurogenesis [35, 36]. In the adult brain, microglia coordinate much of their activity with astrocytes and activate in response to similar stimuli [37, 38]. Dysfunctional signaling between microglia and astrocytes often results in chronic inflammation, a characteristic of many neurodegenerative diseases [39, 40].
Historically, it has been thought that microglia ‘rest’ when not responding to inflammatory stimuli or damage [41, 42]. However, this notion is being increasingly recognized as inaccurate [43]. When not involved in active inflammatory signaling, microglia constantly patrol the neuropil by extension and retraction of their finely branched processes [44]. Microglial activation is often broadly classified into two states; pro-inflammatory (M1) or anti-inflammatory (M2) [36, 45], based on similar phenotypes in peripheral macrophages [46]. M1 activated microglia are characterized by increased expression of pro-inflammatory mediators and cytokines, including inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-1β, often under the control of the transcription factor nuclear factor-κB [45]. Pro-inflammatory microglia rapidly retract their processes and adopt an amoeboid morphology and often migrate closer to the site of injury [47]. Anti-inflammatory M2 activation of microglia, often referred to as alternative activation, represents the other side of microglial behavior. Anti-inflammatory activation is characterized by increased expression of cytokines including arginase 1 and interleukin-10, and is associated with increased ramification of processes [45]. The polarization of microglia into M1 or M2 throughout the brain is well characterized, especially in neurodegenerative diseases [48]. In the AD brain, microglia expressing markers of M1 activation are typically localized to brain regions such as the hippocampus that are most heavily affected in the disease [49]. However, it is important to note that M1 and M2 classifications of microglia may over-simplify microglial phenotypes and may only represent the extremes of microglial activation [50]. It has been more recently proposed that microglia likely occupy a continuum between these phenotypes [39, 51].
Do microglia have multiple roles in AD?
Classical pro-inflammatory activation of microglia has long been associated with AD [39, 49]. Samples taken from late-stage AD brains contain characteristic signs of inflammation, including amoeboid morphology of microglia, high levels of pro-inflammatory cytokines in the cerebrospinal fluid, and evidence of neuronal damage due to chronic exposure to pro-inflammatory cytokines and oxidative stress [52, 53]. The cause of this inflammation may be in response to direct toxicity of Aβ to neurons resulting in activation of nearby microglia and astrocytes [53, 54]. However, Aβ may also induce inflammatory activation of microglia and astrocytes. Activated immune cells are typically present surrounding amyloid plaques [55–57], with such peri-plaque cells exhibiting strong evidence of pro-inflammatory activation [56, 58–60]. The presence of undigested Aβ particles within these activated microglia may suggest that the Aβ peptide itself is a pro-inflammatory signal for microglia [61–64]. In vitro experiments provide supporting evidence for the in vivo studies, with Aβ promoting pro-inflammatory microglial activation [65, 66], and also acting as a potent chemotactic signal [67].
However, it is important to note that although widespread inflammation is characteristic of late-stage AD, it remains unclear what role inflammation could play in early stages of the disease. Some evidence suggests that reducing inflammation through the long-term use of some non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of AD [68]. However, these findings have not yet been verified in clinical trials [69, 70]. Little is understood about how NSAIDs and related compounds affect the delicate balance of pro- versus anti-inflammatory microglial activity within the brain. Although there is considerable evidence to suggest that chronic inflammation may contribute to pathology in the later stages of AD, it is important to note that inflammation normally only represents a small aspect of microglial function. The non-inflammatory functions of microglia may play a more important role in early disease; specifically, microglial functions relating to maintenance of the CNS.
Phagocytosis: A vital role of microglia that may be lost in AD
SYNAPTIC PRUNING: MICROGLIA CAN REGULATE NETWORK ACTIVITY
Recently, a new function has been proposed for microglia. A number of studies have provided evidence that microglia prune synapses throughout life. Microglia are known to remove extraneous synapses during development to ensure that only meaningful connections remain [43]. It was, however, thought that differentiated astrocytes performed the majority of synaptic pruning in the adult brain [91]. The discovery that microglial processes are constantly active within the brain and are often positioned near synapses raised the question of whether microglial synaptic pruning continued throughout life [44, 47, 92–94]. This question was answered in 2014 in a study that demonstrated that microglia do prune synapses into adulthood, and that this activity is important for normal brain function [95]. These findings supported those found a year earlier in a study reporting that ablation of microglia from brain slices increases synapse density and results in abnormal firing of hippocampalneurons [96].
Altered microglial behavior may underlie altered neuronal firing in AD
Altered neuronal activity is an early phenomenon in AD
The cause of DMN hypoactivity in AD is not yet clear; however studies performed in cohorts that are genetically predisposed to AD suggest that DMN hypoactivity is preceded by a period of hyperactivity and increased functional connectivity [123, 136], often manifesting as an absence of normal DMN deactivation during external tasks [137–140]. DMN hyperactivity may interfere with hippocampal memory encoding, leading to the memory deficits that are present in mild cognitive impairment [141, 142]. It has been proposed that hippocampal hyperexcitability in AD may develop as a protective mechanism against increased input from the DMN [142–144]. As AD progresses, the initial hyperexcitability of the DMN and hippocampus may result in hypoactivity due to exhaustion of compensatory mechanisms [123, 136]. Evidence from both transgenic AD mice and longitudinal human studies supports an exhaustion model of hyperactivation leading to later hypoactivation [143, 145–147]. Interestingly, a number of studies report a lower incidence of AD among those who regularly practice meditation which specifically ‘calms’ the DMN [148].
Our understanding of AD as a disease is changing. Historically considered to be primarily a disease of neuronal degeneration, this neurocentric view has widened to encompass non-neuronal cells such as astrocytes into our understanding of the disease process and pathogenesis. A proposed model for microglia in AD is shown in Fig. 2. Microglia perform a wide range of functions in the CNS and although this includes induction of an inflammatory reaction in response to damage, they also have critical roles for maintaining normal function in the brain. Recent evidence shows that microglia regulate neuronal activity through synaptic pruning throughout life as an extension on their normal phagocytosis behavior. The discovery of a large number of AD risk genes associated with reduced immune cell function suggests that perturbed microglial phagocytosis could lead to AD. In our model, altered microglial phagocytosis of synapses results in network dysfunction and onset of AD, occurring downstream of Aβ.
The immune system and microglia represent a novel target for intervention in AD. Importantly, a large number of anti-inflammatory drugs are already in use for other conditions. What is important to know at this stage is exactly how to best target immune cell function. The studies outlined here provide evidence that an indiscriminate dampening down of all microglial activity may result in a worse outcome for individuals by suppressing normal microglial regulatory functions. We currently do not know whether future microglial-based therapies should focus on reducing chronic inflammation or conversely, whether they should be aimed at boosting microglial phagocytosis. It is also likely that future treatment strategies may use a combination of approaches to target Aβ, immune cell phagocytosis and network activity. An increasing view in the AD field is that any drug or therapy needs to be provided very early in the disease process to maximize its beneficial effects. Although we are currently unable to effectively target those at risk of AD at such an early stage, advances in neuroimaging for subtle changes in network activity, or in assays for immune cell function, may provide new avenues for identification of early damage and risk of disease.
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