6: Down Syndrome + Alzheimer's Disease Flashcards
what is a risk factor for down syndrome
Primary risk factor for Down syndrome is advanced maternal age. The likelihood of having DS baby increases as the mother’s age advances, especially after age 35.
What is Alzheimer’s Disease?
progressive neurological disorder affecting brain, leading to cognitive decline+ memory loss. Most common cause of dementia, a syndrome characterized by a decline in cognitive function that interferes with daily activities.
Alzheimer’s symptoms
*Memory loss, especially of recent events
*Difficulty in problem-solving or completing familiar tasks
*Confusion with time/place
*Challenges in communication and language
*Changes in mood or personality
*Difficulty in recognizing familiar people or objects
Management of Alzheimer’s + new research
*no cure for Alzheimer’s, management focuses on improving quality of life + slowing progression of symptoms. Includes medications to manage cognitive symptoms+ behavioural changes. Non-pharmacological interventions such as cognitive stimulation and physical exercise
new research:
* Lecanemab
* stem cell therapy?
Alzheimer’s subtypes
Subtypes:
*most common type: Alzheimer’s disease is the late-onset form, typically manifests age 65+
*Early-onset Alzheimer’s can occur in individuals younger than 65–is linked to specific genetic mutations
Testing of Alzheimer’s
Alzheimer’s disease is diagnosed through combo of med history assessments, physical/neurological examinations, neuropsychological tests.
*Brain Imaging: Imaging techniques, e.g. magnetic resonance imaging (MRI), PET scans, computed tomography (CT) scans, used to identify structural changes in brain and rule out other causes of cognitive decline. Biomarker tests identify specific proteins in cerebrospinal fluid (e.g.Amyloid Precursor Protein, APP)
Hippocampus + medial temporal lobes effected by Alzheimer’s first
what are the 3 types of Down Syndrome
*95% DS individuals have trisomy 21, which means presence of extra copy of chromosome 21 in all cells
*4% have extra copy of chromosome 21, because of Robertsonian translocation (extra copy of chromosome 21 on chromosome 14, one of chromosome 14 loses short arm + that’s replaced by chromosome 21)
*1% have mosaicism w normal + trisomy 21 cell lineages= mixture (usually have M
How is Down Syndrome diagnosed/tested for
DS can be diagnosed prenatally:
*nuchal translucency (non-invasive)= looks at fluid at back of baby’s head on ultrasound– if fluid is 3.5mm-4.4mm 70% chance delivering norm baby. Anything above 4.4mm DS risk[DS babies have increased haluronic acid in extracellular matrix, attratcing H2O in increasing fluid at back of head]
* amniocentesis= gen.testing of cells from amniotic fluid (1 in 100 miscarriage risk)
*chorionic villus sampling (CVS)= gen.testing of tissue from placenta (chorionic villi)
* translocation ds can be inherited from parent to child
*Postnatally, a diagnosis of Down syndrome is typically made based on the characteristic physical features and confirmed through genetic testing e.g. chromosomal karyotype analysis.
what genetic mutation causes Down Syndrome
trisomy 21. Additional chromosome disrupts normal development, leading to characteristic features + health issues.
a baby is born with 46 chromosomes, a down syndrome baby has 47 chromosomes. Babies with Down syndrome have an extra copy of one of chromosome 21, so they have 3 copies and not 2 like normal ppl
How Alzheimer’s worsens + its mechanism of action
Mechanism of Action:
Amyloid Plaques: AD characterized by accumulation of amyloid plaques, which are abnormal clusters of beta-amyloid protein fragments that build up between nerve cells, disrupting cell-to-cell communication and triggering inflammation.
Neurofibrillary Tangles: hyperphosphorylation of tau causes formation of neurofibrillary tangles, twisted fibers of tau protein within neurons, disrupts the transport of essential nutrients and other substances within the brain cells, leading to their malfunction + eventual cell death.
Loss of Neuronal Connections: accumulation of amyloid plaques + neurofibrillary tangles disrupts connections between neurons, leading to progressive loss of synapses & communication between brain cells.
Brain Shrinkage: As disease progresses, brain experiences significant atrophy/shrinkage, due to loss of neurons & breakdown of neuronal connections, leading to decline in cognitive function/memory loss
==all of these lead to progressive cognitive decline
what are the proteins + genes involved in Alzheimer’s disease
*Amyloid Precursor Protein (APP): APP is a transmembrane protein that is cleaved to produce beta-amyloid (Aβ) peptides, which form amyloid plaques found in AD brain.
*Presenilin 1 (PSEN1) + Presenilin 2 (PSEN2): Mutations in the PSEN1 + PSEN2 genes are associated with early-onset familial Alzheimer’s disease (FAD). These genes are involved in the processing of APP and the production of Aβ peptides.
*Tau Protein (MAPT): Tau is a microtubule-associated protein that stabilizes microtubules in neurons. In Alzheimer’s, abnormal phosphorylation of tau leads to the formation of neurofibrillary tangles, which are a hallmark pathological feature of the disease.
*Apolipoprotein E (APOE): APOE is a gene that encodes a protein involved in the metabolism of lipids and cholesterol. The APOE ε4 allele is the most well-established genetic risk factor for late-onset Alzheimer’s, influencing the risk and age of onset of the disease.
*Triggering Receptor Expressed on Myeloid Cells 2 (TREM2): Mutations in the TREM2 gene have been associated with an increased risk of developing late-onset Alzheimer’s disease and other neurodegenerative disorders. TREM2 is involved in microglial function and the immune response in the brain.
*Clusterin (CLU) and Phosphatidylinositol Binding Clathrin Assembly Protein (PICALM): Variations in the CLU and PICALM genes have been identified through genome-wide association studies (GWAS) as genetic risk factors for late-onset Alzheimer’s disease.
1) Which posttranslational modification does the microtubule-binding protein tau undergo which contributes to Alzheimer’s pathology?
2) Which amino acids can undergo this specific post translational modification?
1) In Alzheimer’s –protein tau is hyperphosphorylated [gets an unusually high number of phosphate molecules attached to it]
This modification disrupts normal functioning of tau, causing:
* it loses ability to stabilize microtubules, which are essential for maintaining structure of nerve cells.
As a result, the tau protein clumps together, forming neurofibrillary tangles. These tangles are a key characteristic of AD + are believed to contribute to degeneration/death of nerve cells, leading to cognitive decline
2) (amino acid residues in microtubule binding protein tau) that are commonly affected by hyperphosphorylation include serine and threonine.
*addition of phosphate groups to these serine and threonine residues disrupts the normal function of tau, leading to its detachment from microtubules and subsequent aggregation{process of particles, molecules, or substances coming together to form clusters or larger structures} into neurofibrillary tangle
Aggregation of beta amyloid peptides contributes to the formation of amyloid plaques in the brains of Alzheimer’s patients.
Briefly describe the proteolytic processing that the APP undergoes to produce the cytosolic beta amyloid peptide.
*Amyloid precursor protein (APP) transmembrane protein undergoes proteolytic processing, leading to the production of the cytosolic beta-amyloid (Aβ) peptide, which causes formation of amyloid plaques in Alzheimers brains
proteolytic processing of APP involves the following steps:
Sequential Cleavage: APP is sequentially cleaved by two enzymes known as β-secretase and γ-secretase.
β-Secretase Cleavage: Initially, β-secretase, also called BACE1 (Beta-site amyloid precursor protein cleaving enzyme 1), cleaves APP at the extracellular domain, releasing a soluble fragment called sAPPβ and generating a membrane-bound C-terminal fragment (C99).
γ-Secretase Cleavage: The C99 fragment is further cleaved by γ-secretase within the transmembrane domain, resulting in the production of Aβ peptides of varying lengths, with Aβ40 and Aβ42 being the most common forms.
Formation of Amyloid Plaques: The aggregation of these Aβ peptides, particularly Aβ42, leads to the formation of insoluble amyloid plaques in the brain, which is a key characteristic of Alzheimer’s pathology.
Describe the secondary structure of amyloid fibrils.
Amyloid fibrils are elongated, insoluble protein aggregates characterized by a specific secondary structure known as a cross-beta structure [composed of β-strands running perpendicular to the long axis of the fibril and forming an intermolecular beta-sheet arrangement] = antiparallel structure
*Beta-Sheets: The individual protein chains within fibril are organized into beta-sheets, beta-strands within aligned perpendicularly to the long axis of the fibril. These beta-sheets are formed by the association of neighbouring protein molecules [through intermolecular hydrogen bonding].
*Cross-Beta Structure: The beta-sheets positioned in a crosswise manner, creating “cross-beta” pattern, which can be identified through X-ray diffraction.
*Stability: cross-beta structure provides stability to amyloid fibrils, enabling them to resist degradation and leading to their accumulation in tissues, which is a hallmark of neurodegenerative disease(s)[E.g. Alzheimer’s and Parkinson’s].
Alzheimer’s Disease typically destroys neurons and their connections in the entorhinal cortex and hippocampus.
What cognitive deficit would be observed in these patients?
Memory Impairment: deficits in short-term + long-term memory. This can manifest as difficulty in recalling recent events, learning new information + retaining previously learned facts/ experiences.
Spatial Navigation Impairment: Due to the involvement of hippocampus, individuals with AD may also experience difficulties with spatial navigation + orientation, such as getting lost in familiar surroundings or having trouble finding their way in new environments.
Disorientation: Patients may exhibit disorientation in time, place, or situation, leading to confusion/reduced ability to recognize familiar people, places, objects.
Impaired Learning: impaired ability to acquire new knowledge/skills, affecting individual’s capacity to learn and retain new information.
Decline in Cognitive Function: As disease progresses + more neurons are affected= a decline in overall cognitive function: difficulties with attention, problem-solving+ language comprehension.
SEXUAL DISINHIBITION CAN SOMETIMES MANIFEST AS A RESULT OF COGNITIVE DECLINE. This behavioural change can lead to inappropriate or socially unacceptable sexual behaviour, gestures, or remarks.
