Since its publication, there has been controversy regarding the amyloid cascade hypothesis, questioning its validity and whether or not Aβ accumulation is the primary event that causes AD.
The amyloid cascade hypothesis clearly states that Aβ deposition triggers the formation of NFTs (Hardy and Higgins, 1992). The topographical distribution of Aβ plaques and NFTs in both FAD and SAD show a poor correlation where there is evidence to suggest that Aβ aggregation is not sufficient to cause NFTs. Several groups have shown Aβ deposits to infiltrate the cortex and then progress in an inward fashion while NFTs show an opposite progression (Braak and Braak, 1991; Price et al., 1991). Studies have shown a strong correlation between cholesterol homeostasis and Aβ accumulation and also NFTs formation. Elevation in cholesterol levels in vitro show an increase in APP cleavage whereby affecting the …show more content…
A mutation in APP (A673T) showed to be protective against AD and exhibited a reduction in APP cleavage and therefore decreased levels of Aβ (Jonsson et al., 2012). This study demonstrates that Aβ is involved in initiating AD pathology.
Questions still remain unanswered regarding the amyloid cascade hypothesis and even though drug treatments that are based on this hypothesis have shown a reduction in Aβ load in mouse models exhibiting AD-like symptoms, they have not been successful in human clinical trials (Pimplikar, 2009).
Even though senile plaques and NFTs are considered as the major hallmarks of AD, there are additional pathological mechanisms such as inflammation, oxidative stress, iron imbalance, and cholesterol metabolism that coexist which may trigger or go beyond plaque and NFTs formation. Future research and investigation is needed to understand these processes and how they interrelate with disease progression and furthermore whether they are involved in AD
The amyloid cascade hypothesis clearly states that Aβ deposition triggers the formation of NFTs (Hardy and Higgins, 1992). The topographical distribution of Aβ plaques and NFTs in both FAD and SAD show a poor correlation where there is evidence to suggest that Aβ aggregation is not sufficient to cause NFTs. Several groups have shown Aβ deposits to infiltrate the cortex and then progress in an inward fashion while NFTs show an opposite progression (Braak and Braak, 1991; Price et al., 1991). Studies have shown a strong correlation between cholesterol homeostasis and Aβ accumulation and also NFTs formation. Elevation in cholesterol levels in vitro show an increase in APP cleavage whereby affecting the …show more content…
A mutation in APP (A673T) showed to be protective against AD and exhibited a reduction in APP cleavage and therefore decreased levels of Aβ (Jonsson et al., 2012). This study demonstrates that Aβ is involved in initiating AD pathology.
Questions still remain unanswered regarding the amyloid cascade hypothesis and even though drug treatments that are based on this hypothesis have shown a reduction in Aβ load in mouse models exhibiting AD-like symptoms, they have not been successful in human clinical trials (Pimplikar, 2009).
Even though senile plaques and NFTs are considered as the major hallmarks of AD, there are additional pathological mechanisms such as inflammation, oxidative stress, iron imbalance, and cholesterol metabolism that coexist which may trigger or go beyond plaque and NFTs formation. Future research and investigation is needed to understand these processes and how they interrelate with disease progression and furthermore whether they are involved in AD