Lect 2b: AD
Lect 2b: AD
- Apolipoprotein E (APOE) alleles influence AD related-markers -> APOE4 allele associates with a younger AD onset & greater lifetime AD risk. The underlying biochemical basis for this association is unknown, but hypotheses abound
- The mitochondrial cascade hypothesis
- (Khan, 2004) -> unified explanation -> clinical, biochemical & histologic AD features
- AD & aging epidemiologically intertwined
- R/s strength suggests -> these processes share mechanistic commonalities
- Clinically AD -> x all-or-nothing entity but a continuum
- Mild, moderate, and severe stages are arbitrarily defined
- Conversely, more AD phenomena we recognize, the more likely -> AD puzzle come together.
Senile plaques = Amyloid beta
- peptides of 40 AA -> crucially involved in AD
- peptides result from the APP -> cleaved by beta secretase and gamma secretase to yield Aβ.
- Aβ molecules aggregate -> form flexible soluble oligomers which may exist in several forms.
- γ secretase -> cleaves within the transmembrane region of APP -> gen -> common isoforms -> Aβ40 & Aβ42
- Aβ40 -> more common
- Aβ42 -> more fibrillogenic -> so associated with disease
- APP mutations -> associated with AD -> increased Aβ42 pdn
- Therapy -> modulate β and γ secretases activity -> prevent Aβ42 pdn
Amyloid cascade hypothesis
- Cortical plaques -> consist Aβ protein -> produced via processing of its parent protein APP -> gene encoding APP resides on chromosome 21 -> Specific APP physiologic roles x clear -> but contribute to proper neuronal function & cerebral devt
- (Hardy and Allsop 1991) -> proposed altered APP processing drove Aβ production -> Aβ gave rise to plaques -> plaques induced neurodegeneration -> this neuronal loss -> AD
- Subsequent research failed to show APP mutation -> a common cause of AD -> but other genetic and molecular research findings -> supported amyloid cascade hypothesis -> specifically, PSEN 1 & 2 mutations -> AD
Pittsburgh Compound B (PiB) -> imaging of Amyloid beta
- radioactive analog -> used in positron emission tomography (PET) scans -> image beta-amyloid plaques in neuronal tissue -> provide quantitative information on amyloid deposits in living subjects
- 1st PiB study -> Henry Engler (2002) -> PET scan -> compound was retained in areas of the cerebral cortex known to contain significant amyloid deposits from post-mortem examinations.
- Villain N et al (2012) Amyloid beta -> start of disorder ->posterior temporal & parietal lobe then as dementia progresses -> increased PiB in temporal & frontal lobe
Anti-amyloid beta therapy
- Madani et al 2006
- Neprilysin -> degrades amyloid beta peptide
- Neprilysin KO mice -> AD-like behavioral impairment & amyloid-beta deposition in brain -> since rate-limiting step in amyloid beta degradation -> therapeutic target
- Schenk D (1999) -> Immunization of the transgenic mouse with amyloid beta peptide -> prevented amyloid beta plaque formation
Anti-body mediated clearance
- Sevigny et al 2016 -> generation of aducanumab, a human monoclonal antibody -> selectively targets aggregated A
- Prodromal/mild AD patients -> aducanumab reduced brain Aβ -> dose- & time-dependent manner.
- Slowing of clinical decline measured by Clinical Dementia Rating (MMSE)
- Transynaptic spread via exosomes
- Exosome trf -> small amts of amyloid beta & tau aggregate -> lipid bound -> catch onto next cell & trf damaging proteins to next cell
- Inhibition of exosome spread as therapy
Prion like spread
- Misfolding & aggregation of specific proteins within NS -> most age-associated neurodegen diseases (AD) -> classified as protein misfolding disease -> share key biophysical and biochemical characteristics with prion diseases.
- Prion-like mechanisms in the progression -> Aβ & tau -> induced to misfold and self-assemble -> lesion caused by the pathogenic agents -> spread -> cell-to-cell transportation, including release of intracellular seeds by donor cell & intercellular transport.
- This hypothesis -> new therapeutic strategies -> for AD -> pre-symptomatic phase
Amyloid beta eqbm
- monomer to oligomer transition -> initiates Aβ peptide aggregation
- However -> monomeric state of aggregation-prone peptide -> beyond reach of most experimental techniques & transition lacks understanding
- Normal equilibrium bet CSF and plasma Aβ -> disrupted with initiation of amyloid deposition
- Aβ -> Aβ40 & Aβ42 amino acids -> main components of amyloid plaques -> measured in CSF and plasma
- suggest that the normal equilibrium between CSF and plasma Aβ may be disrupted with the initiation of amyloid deposition in the brain.