Amyloid Plaques - abnormal, extracellular build-up of defective Aβ peptide synthesis (Gouras et al., 2015). The peptide is surrounded by degenerating axonal and dendritic structures, microglia and astrocytes. These structures usually removed by glial phagocytosis, leaving just core of Aβ. Build-up causes inflammation and reactive oxygen species, which damage DNA, proteins and cause apoptosis, leading to neuronal and tissue degeneration in the brain (Walach et al., 2015)
Aβ
- Peptide 36-43 amino acids derived from amyloid precursor protein which codes for Aβ protein, and is coded for by APP gene
- Normal function includes protection against oxidative stress (Zou et al., 2002), apoptosis for genes implicated in cell death (Bailey et al., 2011), anti-microbial activity (Soscia et al., 2010) and responsible for synapse formation, signalling and cell adhesion in neurodevelopment (Minati et al., 2009)
Formation and Synthesis of Aβ
- APP gene on chromosome 21 encodes production APP (St George-Hyslop et al., 1987)
- APP chain approx 700 amino acids
- Normal functions synapse formation (Priller et al., 2006) and neural plasticity (Turner et al., 2003)
- Typical Aβ synthesis - APP cut into two pieces by secretase enzymes α and γ to produce correct chain of Aβ approximately 36-43 amino acids long
- Defective Aβ synthesis - APP chain cut too long by wrong secretase enzyme (β-secretase) :arrow_right: causing issues with the number of amino acids in the Aβ protein :arrow_right: codes for the wrong protein with the wrong functional properties. Approx 40 amino acids long. (Murphy & LeVine, 2010)
- Approx 40% AD have long-form Aβ, only 5-10% typical development (Rodrigue et al., 2012).
Ubiquitination - process where ubiquitin molecules are attached to protein substrates for protein degradation. One of the most important posttranslational modifications (PTMs) regulating stability and functional activity of proteins. (Suresh et al., 2016)
- The long-form Aβ folds incorrectly and is potential toxin.
- Incorrect proteins usually tagged with ubiquitin to be identified by proteasomes
- Proteasomes - protein complexes inside cells that break down damaged incorrectly-folded proteins by proteolysis. This chemical reaction breaks bonds b/w amino acids of mis-folded protein using enzyme proteases, and broken-down aminos are re-synthesised into new proteins using proteases.
- Ubiquitin Failure - example, Autosomal Dominant Cerebellar Ataxias (ADCA) neurodegenerative disorder characterised by progressive degeneration cerebellum, brain stem and spinal cord. Ataxin-1 protein encoded by ATXN1 gene. Some shapes mutant ataxin-1 cannot be broken down.
- AD - reduced activity ubiquilin-1 produces augmented production long-form Aβ and increased neuronal death. Ubiquilin-1 chaperone activity necessary regulating APP and its fragments, so diminished ubiq-1 levels may contribute to AD pathogenesis.
- Ubiq-1 cannot keep up with very high volume long-form Aβ produced in AD, only with small volumes in TD brain (Stieren et al., 2011)
Aβ and Apoptosis
- Proteasome important role apoptosis (Haas et al., 1995)
- Destruction cellular components carried out by specialised proteases known as caspases
- Aβ known to bind to p75 neurotrophic receptor, responds to oxidative stress and stimulated apoptosis (Sotthibundhu et al., 2008). Aβ binds to p75 which causes apoptosis in healthy cells
- APP binds to death receptor 6 (Nikolaev et al., 2009) heavily implicated normal synaptogenesis, axon pruning and normal apoptosis.
- APP acting via DR6 and caspase 6 contributes to AD. Perhaps not long-form Aβ itself, but rather enzymes downstream APP causes AD
- Normal development, amyloid-related mechanisms prune neural connections synaptogenesis early life and then appeaer triggered again by age-related processes later in life to cause apoptosis associated with AD, may lead to shrivelled cortex.
- INABILITY TO CLEAR long-form Aβ FOLLOWED BY COMMENCEMENT OF APOPTOSIS AND PROFOUND NEURONE LOSS
Evidence APP and Aβ
- Build-up Aβ follows similar hierarchical sequence neurodegeneration seen in AD. Begins hippocampus, to final phase in brainstem and cerebellum (Thal et al., 2002)
- Amyloid plaques in Religious Orders Study negatively related to cognitive function and education (Bennett et al., 2003)
- Immunotherapy Aducanumab antibody selectively targets amyloid plaques been shown to reduce Aβ in brains patients AD after one year monthly intervention. Slowing clinical decline compared to control groups too (Sevigny et al., 2016)
- At 78 weeks of trials, significant decrease clinical decline based on clinical dementia rating scores patients high-dosage group (Song et al., 2022)
- APOE4 stimulates Aβ, strongest risk factor AD other than ageing (Li et al., 2015).