Inflammation in Alzheimer's Disaese Flashcards
What is the history of AD?
- First described in 1906
- Alois Alzheimer – German psychiatrist and neuropathologist
- Because interested in 51 year old Auguste Deter at the Frankfurt Asylum → she presented with loss of short-term memory, cognitive and language deficits, auditory hallucinations, delusions, paranoid and aggressive behavior
- Alois performed a biopsy upon her death and stained the brain → identified neurofibrillary tangles and amyloid plaques.
Describe AD characteristics
• Most common form of dementia → dementia is just a symptom of AD, there a multiple forms of dementia
• Two types:
− Early onset AD (65 years) → sporadic
• Progressive → you will always have it, and it will get worse
• Memory loss is the predominant symptom
• Associated with plaques and tangles
• Current treatments (eg, cholinesterase inhibitors) only offer a small symptomatic benefit
• No treatment to cure or prevent disease
• Difficult to work on clinically and in the lab, as by the time the patient gets diagnosed, it is almost too late – people often don’t think their memory loss is AD, so they don’t get tested.
What are the costs of AD to society?
- > 820,000 in the UK suffer with AD
- Overall cost to society in care costs and loss of productivity = £23 billion
- Each patient costs £27,000 per year – more than cancer, heart disease and stroke
- It is an increasing problem because of the ageing population
What are the early and advanced symptoms of AD?
Earliest:
• Short-term memory loss, eg) difficulty remembering facts → happens to everyone with age, so people don’t think they have AD
Advanced: • Long-term memory loss → severe and debilitating, people may forget family members. • Confusion • Irritability • Aggression • Mood swings • Language problems • Withdrawal • Eating problems → appetites can actually be greater, but people think they don’t eat much because of weight loss. But they actually could have metabolic problem.
What is the macroscopic pathology of AD?
- The degeneration is limited to the cortex and doesnot affect other sub-cortical structures the way that Parkinsons and Huntingtons do
- As a result, over the course of 10 years, people with AD can lose as much as 8 to 10% od their brain mass, whereas in healthy people the loss is only around 2%
- Results directly from the shrinking and death of the pyramidal cells of the cortex, which undergo a process of internal degeneration known as neurofibrillary degeneration.
- The shrinkage of the cortex is pronounced in the inner temporal lobe, where the hippocampus is located → hippocampus plays an essential role in language and forming new memories
- As AD progresses, the fluid-filled ventricular spaces become larger
- The pathology is progressive, from mild to severe, and often not diagnosed until the severe stage, by which point it is too difficult to revese all the brain tissue loss.
- Therefore vital to get therapy very early on.
What are the 5 main microscopic pathological hallmarks of AD?
- Amyloid plaques (outside neurons)
- Neurofibrillary tangles (within neurons)
- Selective neuronal degeneration
- Synaptic loss
- Inflammation
How are amyloid plaques formed?
• Insoluble aggregates of beta-amyloid
• Extracellular – in the brain parenchyma
• Formed by abnormal cleavage of amyloid precursor protein by b-secretase and y-secretase
• Normal cleave of APP is by a-secretase, however
➢ APP mutations increase b-secretase cleavage
➢ Presenilin (PSEN) mutations increase y-secretase cleavage
➢ This leads to oligomerisation of a/B peptides, forming plaques
What are neurofibrillary tangles?
• Composed of hyperphosphorylated Tau
− Has 79 potential serine and threonine phosphorylation sites on the longest isoform
− Phosphorylation has been reported on approx.. 30 of these sites in normal Tau
− Phosphorylation of Tau is regulated by kinases, and phosphorylation results in disruption of microtubule organization
− Phosphorylation is developmentally regulated – fetal tau more highly phosphorylated than adult tau
− Hyperphosphorylation of tau can result in the self assemble of tangles of paired helical fliaments and straight filaments
• Intracellular – within the neurons
• Normal function of tau is to bind and stabilize microtubules (microtubule associated proteins) – is involved in the trafficking of neurotransmitters down neurons
• These tangles develop by an unknown trigger
How is AD diagnosed?
• Usually by a set of cognitive tests and a brain scan
• On a scan:
− Can see severely enlarged ventricles and cortical atrophy
− However you do see these things in other neurological disorders, not just Alzheimers
− Can further label the patient with [11C]PIB – a marker of amyloid plaques – but still doesn’t necessarily mean they have AD → some people have plaques and no memory problems
• Patients therefore also undergo memory tests to try and diagnose it
• Definite diagnosis only on post-mortem
What are the suspected causes of AD?
Familial (early onset): • 1-5% of all AD cases • Presents 65 years • Possession of the apolipoprotein E e4 (APOEe4) allele increases the risk • Other risk factors include – note! all of these have an inflammatory component! − Atherosclerosis − Head injury − Hypertension − Diabetes − Obesity − Infection
Describe the role of reactive microglia and astrocytes in AD - with reference to the location of both, their functions, microglia as a diagnostic tool, how the pathology drives activation, microglial diversity and modulating microglia.
Activated microglia:
• Cluster around b-amyloid plaques
• They are the main immunocompetent cells in the brain – they are phagocytic and sense danger
• They are important in the maintenance and plasticity of neuronal circuits, and the protection and remodeling of synapses
• Thus, microglia could play a beneficial role through phagocytosis of amyloid – preventing build up
• However, when activated by pathological triggers, microglia release pro-inflammatory cytokines and ROS that can be neurotoxic
• It could also be that they are busy phagocytosing plaques, and aren’t doing their other jobs like synaptic pruning
→ So not sure if they are detrimental or beneficial!
Activated microglia as a diagnostic tool:
• Use PET imagine – detects pairs of gamma rays emitted indirectly by a positron emitting tracer
• Use PIB as a tracer for b-amyloid plaques, and PK11195 as a tracer for activated microglia
• We can see that there are activated microglia in places very similar to where the plaques are
• There is a hope that maybe early on in alzheimers, we can use the selective marker to look for activated microglia perhaps even before the formation of plaques, and use this as an early diagnostic.
Activated astrocytes:
• Associated with b-amyloid plaques
• Astroyctes normally support neurons
• The conversion to a reactive state may compromise their supportive role
• Activated astrocytes release pro-inflammatory cytokines and ROS that can be neurotoxic
• Activated astrocytes may take up and degraded amyloid beta plaques
How does the pathology (amyloid) drive activaton and cytokine release?
• Aggregated amyloid beta induces IL-1B release from activated microglia in culture
• We know that IL-1B release requires the activity of caspase 1
• NLRP3 is a PRR – it senses danger.
− Release of the accessory molecules allows interaction with its PYD with that of the adaptor molecule ASC
− the CARD domain of ASC binds to the CARD domain of pro-caspase 1, facilitating production of active caspase 1
− This cleaves pro-IL1B to IL-1B
• We know think that amyloid beta aggregates act as a DAMP - this activates the inflammasome
• Amyloid beta induces the release of IL-1B from WT microglia, but not microglia from NLRP3 KO or ASC KP mice → proves it works by activating NLRP3, so it is a DAMP.
• Increased concentrations of active caspase 1 are found in the brains of patients with AD, and in APP/PS1 mice.
Reactive microglia and astrocytes in AD:
• Clear evidence that amyloid-B plaques act as a DAMP and activate the NLRP3 inflammasome via PRRs on microglia
• In response, microglia start to engulf AB fibrils by phagocytosis
• Soluble A-B can be degraded by various proteases including neprilysis and insulin-degrading enzyme, however fibrillar A-B is mostly resistant to enzymatic degradation.
• In sporadic cases of AD, inefficient clearance of A-B has been identified as a major pathogenic pathway
• It is less clear how the astrocytes are becoming activated
• Early astrocyte responses in AD consist of astroglial atrophy, which might have far-reaching effects on synaptic connectivity as astrocytes are central to maintenance of synaptic transmission
• Additionally, astrocytes have a potential role in internalisation and degradation of Aβ in vivo. ApoE is needed for astrocyte-mediated clearance of Aβ, and astrocyte-dependent lipidation of ApoE increases the capability of microglia to clear Aβ.
• Astrocytes also have a role in clearance of soluble Aβ from the parenchyma by paravenous drainage. This pathway depends on the astrocytic water channel aquaporin; deletion of this channel resulted in a substantial decrease in clearance via this pathway.
• We do know that both the microglia and astrocytes become very pro-inflammatory, releasing neurotoxic factors such as IL-1, ROS, TNFa, IL-6, GM-CSF and also nitric oxide…which damage neurons. The resultant dying neurons will release other neuronal injury signals which also act as DAMPs.
• These will be sensed by the microglia, which will result in further neurotoxic factor secretion – and you get a vicious cycle.
• We also still don’t know the interactions of neurofibrillary tangles in this.
• It could be that the timing is different during the course of the disease. Maybe early on, the microglia phagocytose the plaques, but as it gets more severe, they cant do this efficiently because they are becoming overwhelmed with too much beta amyloid, so they start to release pro-inflammatory cytokines (see below).
It is therefore complex – do you inhibit microglia or stimulate? When do you do this?
Microglial Diversity
• Microglia activation is a complex process that results in several phenotypes.
• Outside the CNS, activated macrophages have been categorised as those with a classic, proinfl ammatory (M1) phenotype and those with a noninflammatory, alternative activation (M2) phenotype.
• Classic M1 activation is characterised by increased concentrations of proinfl ammatory cytokines, including TNFα, interleukin 1, interleukin 6, interleukin 12, and interleukin 18, and is accompanied by impaired phagocytic capacity
• The M2 state is characterised by secretion of the antiinfl ammatory cytokines interleukin 4, interleukin 10, interleukin 13, and TGF-β, and increased phagocytic capacity without production of toxic nitric oxide
• Microglia are also likely to exist in a range of phenotypic states during chronic infl ammation
• In the ageing CNS of mice, rats, and primates, microglia show enhanced sensitivity to inflammatory stimuli,32 similar to that noted in microglia in brains with ongoing neurodegeneration. This phenomenon is termed priming. Priming might be caused by microglial senescence and might be associated with ageing.
Modulating Microglia
• The emerging role of microglia activation in Alzheimer’s disease pathogenesis makes these cells a legitimate therapeutic target. However, depending on the circumstances, microglia activation can have both beneficial and detrimental effects. Thus, microglia might have different roles and effects depending on the particular disease stage and which brain region is affected in each model.
• After exposure to a DAMP or PAMP, the acute microglial reaction aims to remove the recognised abnormality or pathological change. In the case of Alzheimer’s disease, this type of inflammatory reaction is sterile because it involves the same receptors but no living pathogens.
• Under normal circumstances, such a reaction quickly resolves pathological changes with immediate benefi t to the nearby environment. However, in Alzheimer’s disease, several mechanisms, including ongoing formation of Aβ and positive feedback loops between infl ammation and APP processing, compromise cessation of infl ammation. Instead, further accumulation of Aβ, neuronal debris, and, most probably, further activating factors establish chronic, non-resolving inflammation.
• As an intracellular regulator of microglial function, expression of the autophagy protein Beclin 1 is reduced in the brains of patients with Alzheimer’s disease. Reduction of Beclin 1 expression in vitro and in vivo interferes with effi cient phagocytosis.
• Plasticity of the microglial phenotype is of fundamental importance, since resolution of infl ammation clearly involves conversion to an alternative (ie, similar to M2) activation state associated with tissue repair, phagocytosis, and anti-infl ammatory actions. Conversion of microglia from detrimental to benefi cial players might be achieved by modulation of proinfl ammatory signalling pathways such as the NLRP3 infl ammasome. Successful modification of these pathways, however, necessitates that they are exclusively restricted to microglia and do not have crucial functions in other cell types.
Describe the role of chemokines in AD
• Chemokines have been suggested to regulate microglial migration to areas of neuroinfl ammation, thereby enhancing local infl ammation in Alzheimer’s disease.87 In Alzheimer’s disease, upregulation of CCL2, CCR3, and CCR5 in reactive microglia has been reported,88,89 whereas CCL4 has been detected in reactive astrocytes near Aβ plaques.
Describe inflammation in the NVU in AD
- vascular pathological change is an important risk factor for development of Alzheimer’s disease.
- Moreover, Alzheimer’s disease is associated with distinct infl ammatory, functional, and morphological alterations of cerebral blood vessels and perivascular glia and neurons (the neurovascular unit).
- These changes are induced by combined effects of Aβ deposits and ultimately lead to decreased cerebral blood fl ow and impaired functional hyperaemia (ie, the ability of local blood fl ow to increase in response to neuronal activation).
- Chronic cerebral hypoxia is further amplified by blood-borne factors such as platelets, which are chronically activated in models of, and patients with, Alzheimer’s disease, ultimately resulting in microinfarcts and neuronal injury.
- Moreover, the combination of mild hypoxia, infl ammation of the neurovascular unit, and progressive Aβ accumulation in brain parenchyma, induces upregulation of AGER (also known as RAGE), which mediates Aβ transport into the brain across the blood–brain barrier.13
Describe the role of traumatic brain injury in AD
- Several studies have established traumatic brain injury as a risk factor for development of Alzheimer’s disease.
- Experimentally, traumatic brain injury aggravates learning and memory defi cits and deposition of Aβ inmouse models of Alzheimer’s disease.
- Results of animal and human studies have shown that microglia activation can persist for months or years after traumatic brain injury.
- Some cytokines implicated in traumatic brain injury can potentially increase B-secretase concentrations, thereby shifting APP processing to amyloidogenic generation of Aβ.
Describe a role for peripheral inflammation AD
• Increases in pro-inflamamtory mediators in the circulation
• Changes in the responsiveness of peripheral immune cells (eg, DCs)
• Increase in APPs → raised CRP increases AD risk and predicts progression from mild cognitive impairment to AD
• Infections can make AD symptoms worse – people often don’t go back to how they were pre-infection
• Studies have shown an infiltration of peripheral MNCs associated with amyloid plaques In mouse models
− Ablation of CD11+ cells in the APP/PS1 model showed that peripheral mononuclear phagocytes have an important role in reducing the build up of AB plaques
− Restriction of entry by deletion of CCR2 lead to increased plaque load
− However, many of these studies use bone marrow irradiation and this is likely to damage the BBB – and a further study where the brain was shielded did not report any cerebral infiltration by peripheral macrophages
• Obesity :
− increases a patients propensity to acquire bacterial or viral infections, and thus directly increases the likelihood of systemic inflammation
− white adipose has a high percentage of activated macrophages secreting proinflammatory cytokines
− Midlife obesity identified as a risk factor for AD
− As a possible result of obesity, T2DM accelerates memory dysfuncton in a mouse model of AD
− Obesity associated reduced gut microbial diversity associated with increased concentraitons of pri-inflammatory cytokines
