What are the two common and classic neurodegenerative diseases?
(1) Alzheimer’s Disease
(2) Parkinson’s Disease
What is the difference between the healthy aging and dementia?
(1) dementia is not the healthy aging but the pathological insult to the brain structure and function
(2) Dementia is the loss, usually progressive, of cognitive and intellectual functions, without impairment of perception or consciousness; caused by a variety of disorders including severe infections and toxins, but most commonly associated with structural brain disease, characterized by disorientation, impaired memory, judgment, and intellect.
What morphology of the AD infected brain section?
(1) Substantial loss of brain volume: great loss of neurones and white substances
(2) Enlarged ventricles
(3) Widened sulci
(4) Thinned Gyri
(5) the neurones for thinking and memory is not replaceable by the neural stem cells
(6) hippocampus degrades over the year and eventually leads to the poor memory
Alzheimer’s disease pathology at the cellular level
(1) Neuronal loss
(2) Synaptic damage
(3) Amyloid plaques
(4) Neurofibrillary tangles: fibrous structure
compare and contrast the amyloid plaques and neurofibrillary tangles
(1) amyloid plaque: composed of mainly the beta-amyloid peptide and found extracellularly in mixture with other proteins such as APOE
(2) neurofibrillary tangles: found intracellularly, composed of hyperphosphorylated tau in paired helical structure
what gene mutations can cause the autosome-dominant, early-onset AD?
(1) APP (amyloid precursor protein)
(2) PS1 (presenilin 1)
(3) PS2 (presenilin 2)
What gene mutation accounts for the late-onset AD occurance?
(1) APOE4 allele
(2) TREM2 allele
the mechanism of amyloid folding and aggregation
(1) amyloid precursor protein(APP) is expressed not only in the brain, but also epithelial cells, blood vessel cells, its role is not yet known.
(2) BACE (beta secretase) cleaves the APP at specific sites, the conjugation of the beta/gamma-secretase generates the alpha-beta amyloids with various lengths, different lengthed amyloids aggregate and precipitate.
(3) the gamma-secretase bound in the membrane cleaves the transmembranal segments of the APP at amino acid site 40 or 42
(4) Generation of amyloid-β (Aβ) from the amyloid precursor protein (APP). APP cleavage by beta-secretase generates the N terminus APPsβ and intramembranous beta-stub which can be cleaved by the gamma-secretase to generate the Aβ. APP cleavaged by gamma-secretase gives the C terminus of amyloid-β. APP cleavaged by a-secretase precludes Aβ formation, the more the Aβ peptides accumulating, the higher the risk of getting AD. amyloid-beta is toxic to the neurones and impairs their function. Sometimes, the side effects can be resulted from the chain reaction.
What gene alteration events can increase the probability of the mutation?
Gene duplication can introduce additional gene coding for the APP. Duplication of the APP gene and missense mutations in the APP gene cause inherited forms of Alzheimer’s disease and cerebral amyloid angiopathy. Twenty known missense mutations in APP cause human diseases, the mutations can affect the production of alpha-/beta/gamma-secretase or the cleavable site on the APP but little effects are posed the shape of the APP.
describe the architecture of the presenilin enzyme
Presenilins are membrane-embedded protease enzymes that cleave other transmembrane proteins in a regulated manner. The few asparic acid residues located at the transmembrane domain conducts the proteolysis on the substrate peptide. Mutation at the presenilin-coding gene increases the dosage of the APP, therefore more likely to incur AD.
What is amyloid?
(1) Many proteins enter the amyloid state, in which they form elongated fibers, with spines consisting of many-stranded and anti-parallel beta sheets. Amyloid fibers are unbranched, usually extracellular, and found in vivo; the fibers bind the dye Congo Red and then show green birefringence when viewed between crossed polarizers. Beta-sheets stack to form insoluble amyloid plaque.
(2) Amyloid fibers display the cross-beta fibre diffraction pattern by the X-ray directing to the folded beta sheets. By this definition, fewer than 25 amyloid-forming proteins have been identified and associated with serious diseases, including amyloid-beta peptide, some even present in the bloodstream.
What is tau protein?
(1) Tau is an intrinsically disordered protein that can be alternatively spliced at N terminal exons (N1, 2) and the microtubule repeat domains (R). The domains of tau bind many different types of molecules, suggesting a central role in signaling pathways and cytoskeletal organization. tau can be associated with the actin, some signalling complexes, kinase proteins, SH3 domains, some of them are in the nucleus but majority of them are bound to the tubuling. Microtuble transports the motor protein up and down the axon to carry cargo, motor kinase is responsible for transporting the cargo
(2) the tau protein consists of two domains: C-terminus domain in which four repeats are included(R1, R2, R3 and R4) and N-terminus domain with two repeats(N1 and N2). One gene controls the order management of the repeats in the C-terminal domains.
(3) aggregated tau in AD patients is in the paired helical structure, the appearance is like the C-shape in twin
what changes will take place in an AD-positive cell?
(1) Some demantia have hyperphosphorylated tau precipitation but the amyloids are not found as a reuslt of various tauopathies. Declined neuronal function taking place along the amyloid formatioin, for example, the AD, either downstream or upstream the amyloid formation.
(2) One of the hypothesis assumes that the tau is related to microtuble stability. Hyperphosphorylated tau precipitates and somehow causes the microtubule dissociation, even neurone degradation due to the microtubule supportive role as a cable, but chopping the tau gene seems to do nor harm to the microtubule.
Microtubule also acts as an kinase highway transporter whose disfunctioning can lead to unabilibity of delivering cargo by kinase from body cell to destroyed terminal.
What are the rare gene mutation which occurs with an increase in probability of AD?
The tau gene, known FTLD17-associated mutations and sites of hyperphosphorylation
What methods could be the hyperphosphorylated tau protein be detected from the patient’s brain?
(1) stain the brain for tau hyperphosphorylation
(2) incubate the thin brain section with antibodies for the hyperphosphorylated tau
(3) the tau filaments stack up in C-shaped intwined arrangment, the in-between interaction is stabilised by the antiparallel beta sheets.
(4) If the tau is about to be hyperphosphorylated, the antiparallel beta sheets are somehow condensed to strenthen the interaction.
Any other reasons inducing AD except the amyloid and the tau deposit?
(1) apoE4 is the strongest risk factor
(2) apoE4 codes for the lipid/fat-binding protein, for example, the cholesterol-binding protein.
(3) four forms of the apoE4: alpha, beta, gamma and elipson. Increase in the homologous apoE4 potentially cause the rise in risk of getting AD. e.g. 4/4 form combination gives rise to the sharpest increase in the chance.
(4) TREM2 is accompanied with the enhanced activity of the amyloid seeding, meanwhile, the associated apoE protein and microglial clustering the newly synthesized seeds reduce
How do the alpha beta amyloids convert into the insoluble phase from the soluble phase?
(1) the alpha beta amyloid monomers oligomerise into the oligomers and eventually turns into the seed by unkown mechanism, alternatively, the seeds can be formed directly from the monomers by nucleation.
(2) Seeds are already intermediate aggregate which is insoluble so that the seeds are readily aggregate by an inversible process known as fibrillogenesis to form fibrils, fibrils can further aggregate to form amyloid plaque. Otherwise, seeds can be cooperated with apoE proteins in complex, the apoE-seed complex can also be resulted from the fibrils. In the end, apoE-seed complex in which the abundance of E4 is higher than that of E3 aggregates to form the amyloid plaque.
What are the glial cells? What are their roles?
(1) microglia is a component of the immune system in the brain, acting as a macrophage to prevent the antibodies from reaching the brain blood barrier. In disease states, the microglia are normally over-activated, some neurones may potentially be removed because of the over-activation. The microglia urveillance includes the programmed cell death, pagocytosis of the amyloid plaques, neuronal plasticity, synaptic pruning.
(2) if the inflammantary stress is sensed by the healthy aging neurone, the glia tend to destroy the neurones since they are over-activated. Meanwhile, axonal varicosities(axonal swelling), APP synthesis and the tau hyperphsophorylation increase.
(3) In the case for the aged neurones or the chronic or the repeated inflammatory stress, the axonal transporting ability is impaired, with APP accumulating and the axonal swelling which is due to the axonal varicosities. Microglial priming to the neurone causes the neuronal destruction and tangles’ formation. In the late stanges, the microglial clearance ability of endocytosing the dystrophic debris and neutris impairs so aberrant APP processing efficiency declines, the plaque is therefore formed. Meanwhile, hyperphosphorylated tau filaments gradually accumlate in the cell body. The three hypothetical symptoms of the AD pathology are respectively the neuroinflammation, sensile plaques and the neurofibrillary tangles.
What are the TREM2 molecules? What are their roles?
TREM2 would be the receptor for the amyloid beta and for the cholesterol, moreover, the molecule may be required as the component in recognising the amyloid plaque. Without the TREM2 bound at the glial cells, the pagocytpsis is not able to be accomplished. TREM2 can trigger the innate immunity of the microglia
What are other external factors causing the AD?
(1) aging
(2) gene
(3) diet
(4) exercise
(5) gut microbime
(6) sleep-wake cycle: the amount of alpha-beta increases with decreased sleeping time, extracellular space between glia feet and surface of capillary increases in the NREM sleep in compared with the wake state. More waste fluid flows down the outside of the vessels more during the NREM sleep.
current and future therapies for AD? What difficulties may be encountered during the drug development?
(1) Currently, there are no effective treatments
(2) Acetylcholinesterase inhibitors(inhibit the breakdown of acetylcholine by acetylcholinesterase) and NMDA receptor antagonists increase cognitive
performance transiently. Acetylcholine is a neurotransmitter which can only promote the short-term memory temporarily
(3) AD begins to develop 10–20 or more years prior to recognizable clinical signs.By the time AD is recognized, substantial synaptic, neuronal degenerative and inflammatory changes have already occurred. For therapeutics to delay or prevent AD, patients will need diagnosing at the stage of preclinical AD (i.e. presence of AD neuropathology but no clinical manifestations) or during early symptomatic AD, and then be given disease-modifying agents.
(4) If the early stage AD sympotoms are interpretable, the disease can be relieved easier.
(5) The below are disease modifying agents which are to be developed:
Beta secretase inhibitors Inhibit b-amyloid
Gamma secretase inhibitors Inhibit b-amyloid
Amyloid lowering antibodies less amyloid burden
Neurotrophic molecules neuronal survival
Anti-inflammatory drugs less brain inflammation
Phosphorylation inhibitors reduced tau hp
Nuclear hormone receptor modulators
