Alzheimer´s disease Flashcards
normal brain ageing - functional
Healthy brain ageing involve cognitive functions but particularly relate to executive and attentional functions.
Semantic and verbal knowledge, by contrast, appear to be relatively preserved from age-related change
- Difficulty learning something new
- Loss in multitasking activity
- Impaired memory
Normal brain ageing - physiological changes (grey matter)
Age-related grey matter changes include:
- cortical thinning
- decreased brain tissue surface
- decreased brain density - neuron atrophy (pre-frontal and hippocampus mainly) –> highly region-dependent
- Reasons for this decline are a shrinkage of neurons, a reduction of synaptic spines, and a reduced number of synapses rather than neuronal loss
normal brain ageing - white matter
Mainly, deterioration of fiber connections caused by the loss of myelin. As a consequence, the length of myelinated axons and white matter volume are reduced in older adults
• Older connections are smaller and more prone to degradation
- Side note (!!!): dysregulation of neurotransmitters
Alzheimer’s disease - definition
- Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to carry out the simplest tasks.
- The main pathological symptoms are
• Loss of memory
• Difficulties in performing everyday task
• Aggressive behaviour
• Hallucinations
• Paranoia
familial (EOAD) vs. sporadic (LOAD)
familial:
- starts around 40y
- 5% of AD cases
- inherited
- genetics (chromosomes 1, 14 and 21)
- linked to down syndrome
sporadic:
- > 65y
- 95%
- not hereditary
- might have genetic causes
- environmental risk factors
the molecular and cellular causes of AD
- Neuronal loss
- Neurofibrillary tangles
- Blood brain barrier disruption
- Lipid disbalance
- Neuroinflammation
- Senile plaques
senile plaques
APP is a transmembrane protein which in AD is cleaved by beta-secretase (on the extracellular domain) and gamma-secretase (intracellular) to create beta-amyloid fragment of 40/52 amino acids long which form extracellular neurotoxic plaques
neurofibrillary tangles
In AD, tau protein (on the microtubules in neurons) are hyperphosphorylated and thereby lose their affinity for the microtubules.
The tau now accumulates in the neuron forming neurotoxic tangles and leaving the microtubule dysfunctional - making transport, to and from, the soma very difficult
disbalance of lipids
There are different class of lipids which play important functions in the physiology and the pathology of the brain
• Cholesterol: in the membranes of neurons there are lipid rafts in which many proteins are clustered and stabilised by cholesterol
- This includes; APP and the beta and gamma secretases that cause senile plaque formation
• Sphingolipids: second messengers that influence many signalling cascades
- In AD there is disbalance between subclasses of sphingolipids –> anincrease in ceramide and decrease in sphingomyelin
Sphingomyelin is broken down by ASM (acid sphingomyelinase) into ceramide - ceramide induces apoptosis and thus neuronal loss
Ceramide also increase beta-secretase expression which leads to more beta-amyloid formation which leads to increased ASM activation/translocation which produces more ceramide –> ceramide cycle
- Phospholipids
- Gangliosides
blood-brain-barrier disruption
BBB dysfunction leads to cerebral micro bleeds reflecting loss of cerebrovascular integrity
- In AD pericytes and tight-junctions are lost which lead to the micro bleeds (cause ROS) and brain extraversion of blood-derived substances (these include; plasmin, albumin, thrombin, fibrin, pathogens, etc.)
• There is also loss of function of efflux transporters
neuroinflammation
During AD there is proliferation of both microglia and astrocytes which induces inflammation
- So the innate immune cells of the brain are activated and release pro-inflammatory cytokines (TNFα, IL-1, IL-6, IL-18), chemokines and interleukins which attract more leukocytes to the brain
- The inflammatory state causes tissue damage, chronic inflammation increasing the severity of the disease
genetics and familial Alzheimer’s disease
- Early-onset AD is caused by a number of different single-gene mutations on chromosomes 1, 14 and 21
• PS-2 (1)
• PS-1 (14)
• APP (21)
genetics and sporadic AD
- APOE4 is the most significant risk gene for late-onset Alzheimer’s disease
- APOE, apolipoprotein E, comes in three variants (alleles) 2, 3, and 4.
- APOE binds to cholesterol and lipids in cells’ environments.
- In AD it is less efficient at clearing the Aβ –> this is the APoE4 allele
Amyloid precursor protein
The APP gene encodes amyloid precursor protein, a transmembrane protein whose proteolysis gives rise to Aβ peptides
- The mutations in APP gene promote the formation of toxic Aβ, which will accumulate and form the senile plaques
• The mutations do this by creating a cleavage site in the APP protein for beta-secretase
• Normally only alfa-secretase is able to cleave APP’s extracellular domain which does not produce beta-amyloid
Presenilin 1 and 2
Mutations in the Presenilin 1 (PS1) and Presenilin 2 (PS2) genes account for the majority of the cases of familial early-onset AD
- Presenilin proteins influence (complex) the γ-secretase– mediated processing of APP, cause a selective increase in the levels of highly Aβ42 species, and accelerate Aβ deposition in the brain
