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Overview
- Umbrella term for a range of conditions that primarily affect neurons in the brain.
- Characterised by progressive loss of structure and/or function of neurons, including neuronal death.
- Neurons cannot usually divide and replicate therefore cannot be replaced.
- As such, neurodegenerative diseases are usually progressive and incurable.
- Commonly associated with movement deficits (ataxia) and/or mental deficits (dementia).
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Types of neurodegenerative diseases
- There are many types of neurodegenerative diseases, including:
- Alzheimer’s disease (AD) and other dementias
- Parkinson’s disease (PD) and PD-related disorders
- Prion disease
- Motor neurone diseases (MND or ALS; amyotrophic lateral sclerosis)
- Huntington’s disease (HD)
- Spinocerebellar ataxia (SCA)
- Spinal muscular atrophy (SMA)
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Dementia
- Describes a set of symptoms that vary depending on the region of the brain affected.
- Difficulty with thinking, problem solving and language
- Changes in mood and behaviour
- Memory loss
- Results from a loss of neurons.
- Different types of dementia:
- Alzheimer’s Disease (most common ~70%)
- Dementia with Lewy Bodies (DLB or LBD)
- Vascular Dementia (mini strokes)
- Frontotemporal Dementia (FTD; Pick’s Disease)
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Alzheimer’s Disease (AD)
- Progressive cognitive decline over several years ~ 8.5 years before death
- Marked selective neuronal degeneration and synaptic loss, particularly in the hippocampus, amygdala and temporal neocortex.
- Affects several cognitive domains including memory, visuo-spatial skills and executive function (e.g. attentional control, inhibitory control, reasoning, problem solving, planning).
- Later stage disease is associated with complex behavioural and psychological needs that require specialist care
- Patients can be aware
- Factors involved:
- Age = risk doubles every 5 years after 65.
- Gender = increased risk in females of all ages (lack of oestrogen? early HRT may help)
- Ethnicity = Hispanic, African, African-Caribbean seem to develop more often. These ethnicities are also more prone to diabetes/stroke
- Lifestyle = smoking, lack of exercise, unhealthy diet, alcohol, head injuries (repeated) [diabetes and stroke risk factors]
- Genetics = no strong link but mutation in APOE e4, and TREM2.
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Early-onset Alzheimer's
- 5-10% of cases
- 40's/50's
- Rapid progression after onset
- Usually inherited: mutations in APP, PSEN1, or PSEN2 gene.
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Pathological hallmarks (Alzheimer's): Extracellular senile plaques
- Bodies in the brain found outside neurons
- Contain Amyloid-β-Peptide (Aβ)
- Member of a family of amyloid polypeptides which, following their misfolding, interact inappropriately with specific cell types to invoke degenerative disease.
- ==> Prion diseases such as BSE and in Huntington’s Chorea.
- Amyloid Precursor Protein (APP)
- Occurs naturally and has an important role during development in cell differentiation and possibly synapse development.
- Role of APP in brain of adults is not clear.
- Expressed by neurons in response to cell injury and used as a marker for axonal damage after head injury
- APP expression is increased in affected regions of the brain in temporal lobe epilepsy
- APP is cleaved by secretase enzymes
- Beta and Gamma secretase cleave APP (instead of sAPP) off and Amyloid B monomer
- Mutations in PSEN1/2 increase the likelihood of this cleavage (heritable?)
- > Aβ monomers transition from a random coil or α-helix conformation to a β-hairpin.
- >This facilitates a polymerisation reaction which forms short, soluble metastable intermediates called oligomers
- > The oligomers assemble to form an oligomeric nucleus which can be rapidly extended by further monomer addition to form curvilinear protofibrils.
- > These then bundle together to form the large insoluble cross-β-sheet fibrils which accumulate in plaques (β amyloid senile plaques).
- The true toxic Aβ species is not known.
- Now proposed that the Aβ oligomer intermediates are toxic from an early stage in AD.
- A wide variety of oligomers have been identified as neurotoxic.Not really known how Amyloid-β causes neurodegeneration
- May interfere with synaptic transmission
- May induce a damaging inflammatory response
- May also damage microvasculature of the brain and make vascular dementia more likely
- Microfilm produce immune response to aB oligomers = can lead to cell death
- Apolipoprotein E (APOE) is involved in breaking down Amyloid-β protein
- APOE ε4 is less efficient than other APOE alleles so carriers of this are more likely to: have more Amyloid-β, develop β amyloid plaques
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Pathological hallmarks (Alzheimer's): Neurofibrillary tangles and Tau proteins
- Intra-neuronal neurofibrillary tangles - comprised of aggregations of the cytoskeletal protein tau (inside neurons)
- Tau proteins stabilize microtubules – part of the cytoskeleton - abundant in distal portions of axons in the CNS.
- Microtubules:
- > provide structural support within cells
- > transport nutrients, vesicles and mitochondria within the cell.
- Tangles are probably initiated by plaque formation -> presence of plaques is associated with hyperphosphorylation of tau
- Hyperphosphorylated tau becomes dissociated from microtubules and
- aggregates inside neurons
- Loss of tau disrupts microtubule function and leads to apoptosis – programmed cell death
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Alzheimer’s Disease and Type-2 Diabetes
- Patients with type-2 diabetes have twice the risk of developing AD.
- Insulin binding the insulin receptor (IR) allows glucose uptake by cells (including neurons)
- IR and insulin-like growth factor 1 receptor (IGF-1R) are also linked to intracellular signalling pathways via the insulin receptor substrate 1/2 (IRS-1 / IRS-2)
- > IRS 1/2 released when insulin binds w/ receptor
- Insulin resistance results in chronically high blood sugar
- Chronically high blood sugar is associated with a wide range of serious negative health issues - associated with local vascular damage in organs
- Amyloid-β and insulin share a common sequence recognition motif.
- Aβ is therefore a direct competitive inhibitor (antagonist) of insulin binding to the Insulin receptor (IR).
- Aβ therefore compromises insulin receptor activation and thereby the intracellular pathways that control glucose homeostasis.
- Brain is extremely metabolically active and needs lots of glucose
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