Current Insights into Molecular Mechanisms of Alzheimer Disease and Their Implications for Therapeutic Approaches

@article{VanBroeck2007CurrentII,
  title={Current Insights into Molecular Mechanisms of Alzheimer Disease and Their Implications for Therapeutic Approaches},
  author={Bianca Van Broeck and Christine van Broeckhoven and Samir Kumar-Singh},
  journal={Neurodegenerative Diseases},
  year={2007},
  volume={4},
  pages={349 - 365}
}
During the last 10 years, a lot of progress has been made in unraveling the pathogenic cascade leading to Alzheimer disease (AD). According to the most widely accepted hypothesis, production and aggregation of the amyloid β (Aβ) peptide plays a key role in AD, and thus therapeutic interference with these processes is the subject of intense research. However, some important aspects of the disease mechanism are not yet fully understood. There is no consensus as yet on whether the disease acts… 
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References

SHOWING 1-10 OF 137 REFERENCES
Genetics and pathology of alpha-secretase site AbetaPP mutations in the understanding of Alzheimer's disease.
TLDR
How pathologies linked to the Dutch and Flemish AbetaPP mutations have helped in understanding the role of CAA in dementia and in the development of dense-core plaques is discussed.
Tau protein phosphorylation as a therapeutic target in Alzheimer's disease.
TLDR
Key challenges in developing effective therapeutic agents include identification of the relevant kinase(s) responsible for aberrant tau phosphorylation in AD, synthesis of inhibitors selectively targeting those kinases and establishment of appropriate animal models.
Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse
TLDR
It is reported that immunization of the young animals essentially prevented the development of β-amyloid-plaque formation, neuritic dystrophy and astrogliosis, and treatment of the older animals markedly reduced the extent and progression of these AD-like neuropathologies.
Aβ40 Inhibits Amyloid Deposition In Vivo
TLDR
The protective properties of A β40 with respect to amyloid deposition suggest that strategies that preferentially target Aβ40 may actually worsen the disease course and that selective increases in Aβ 40 levels may actually reduce the risk for development of AD.
Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios
TLDR
Support for the hypothesis that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on Aβ levels in the presence of normal PS1 alleles is provided.
Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease
TLDR
Aβ immunization reduces both deposition of cerebral fibrillar Aβ and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of Aβ in the brain, which implies that either a ∼50% reduction in dense-cored Aβ plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic Aβ species.
Wild-type Presenilin 1 Protects against Alzheimer Disease Mutation-induced Amyloid Pathology*
TLDR
These findings establish a protective role of the wild-type PS1 against the FAD mutation-induced amyloid pathology through a partial loss-of-function mechanism.
Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1
TLDR
Results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of Aβ42(43) in the brain.
BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.
TLDR
The findings that BACE is the primary beta- secretase activity in brain and that loss of beta-secretase activity produces no profound phenotypic defects with a concomitant reduction in beta-amyloid peptide clearly indicate that Bace is an excellent therapeutic target for treatment of AD.
...
...