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

  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},
  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… 
Emerging amyloid beta (Ab) peptide modulators for the treatment of Alzheimer's disease (AD)
Considerable research effort has focused on secretase-mediated mechanisms of βAPP processing, and the latest pharmacological strategies have used selective Aβ-peptide-lowering agents (SALA) to provide therapeutic benefit against A β-initiated neurodegenerative pathology.
Alzheimer’s disease pathology was well studied using transgenic animal models in order to characterize the molecular deficiencies observed in humans and a link between beta-amyloid plaques and alfa-synuclein was found.
New intracellular mechanisms involved in Alzheimer's disease and frontotemporal dementia
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GSK-3 inhibitors: a ray of hope for the treatment of Alzheimer's disease?
Data clearly identify GSK-3 inhibitors as one of the most promising new approaches for the future treatment of AD and a reduction of the aberrant over activity of this enzyme might decrease several aspects of the neuronal pathology in AD.
Amyloid beta (Aβ) peptide modulators and other current treatment strategies for Alzheimer’s disease (AD)
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  • Biology, Medicine
    Expert opinion on emerging drugs
  • 2012
This review is a compilation and update on current pharmacological strategies designed to down-regulate Aβ42 peptide generation in an effort to ameliorate the tragedy of AD.
Basic pathologies of neurodegenerative dementias and their relevance for state-of-the-art molecular imaging studies
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  • Medicine, Biology
    European Journal of Nuclear Medicine and Molecular Imaging
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An overview of molecular key pathologies, which are currently regarded to be strongly associated with the development of different dementias, will be shortly summarized; it will be discussed how state-of-the-art imaging technology can assist to visualize these processes now and in the future.
Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer's disease (AD).
The contribution of a defective microglial-based TREM2 transmembrane sensor-receptor system to amyloidogenesis in AD that is in contrast to the normal, homeostatic clearance of Aβ peptides from the human CNS is discussed.
Reassessing the amyloid cascade hypothesis of Alzheimer's disease.
  • S. Pimplikar
  • Biology, Psychology
    The international journal of biochemistry & cell biology
  • 2009
Perspective The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease
It is proposed that AD, which occurs in elderly, already vulnerable brains, with multiple age-related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch-related angiogenesis, which causes the atrophy of neural structures.
The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease


Genetics and pathology of alpha-secretase site AbetaPP mutations in the understanding of Alzheimer's disease.
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.
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
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
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
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
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*
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
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.
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.