alzheimers amyloid

What is the Amyloid Cascade Hypothesis?

It suggests that altered processing of APP generates increasing levels of Aβ42, leading to inflammation, oxidative injury, tau aggregation, and neuronal death in Alzheimer's disease.

What are senile plaques?

They are dense cores of aggregated Aβ surrounded by dystrophic neurites, activated microglia, and fibrillary astrocytes, identified by silver stain.

What is the role of Amyloid Precursor Protein (APP)?

APP is a transmembrane protein cleaved by secretases, involved in nervous system development, synaptogenesis, and synaptic plasticity.

What is the function of alpha-secretase?

It cleaves APP extracellularly to generate the non-amyloidogenic fragment P3.

What is the role of beta-secretase (BACE1)?

BACE1 cleaves APP in endosomes, generating amyloidogenic fragments that lead to Aβ production.

What is the function of gamma-secretase?

It is a complex that cuts within the transmembrane domain of APP, releasing Aβ fragments and the amyloid intracellular domain (AICD).

What are the differences between Aβ1-40 and Aβ1-42?

Aβ1-42 is more toxic than Aβ1-40 and is associated with increased aggregation and plaque formation in Alzheimer's disease.

What happens when alpha-secretase cuts APP first?

It prevents the generation of Aβ because the β-cleavage site is in the sAPPα fragment.

What are the normal physiological conditions regarding Aβ levels?

Under normal conditions, Aβ levels are low, and the alpha-secretase pathway predominates, potentially providing neurotrophic effects.

How does Alzheimer's disease affect Aβ levels?

In Alzheimer's disease, Aβ levels are greatly increased, with the beta-secretase pathway predominating, leading to cholinergic signaling interference.

What are the potential outcomes of missense mutations in APP?

They can increase overall Aβ production, alter Aβ properties, or change Aβ ratios, particularly increasing Aβ42.

What are some therapeutic approaches for Alzheimer's disease?

Therapeutic approaches include γ-secretase enhancers, β-secretase inhibitors, α-secretase enhancers, amyloid immunotherapy, NSAIDs, antioxidants, and gene therapy.

What are Aβ oligomers believed to do?

They may induce toxic events through receptor interactions, increasing membrane permeabilization, and impairing cellular functions.

What is the significance of the neurotrophic fragment APPsα?

APPsα upregulates protective pathways, inhibits neuronal apoptosis, and plays a crucial role in synaptic plasticity and memory.

What is the role of activated microglia in Alzheimer's disease?

Activated microglia are involved in the inflammatory response and can contribute to neuronal damage in Alzheimer's disease.

What is the impact of Aβ on cholinergic signaling?

Aβ can interfere with cholinergic signaling, exacerbating cognitive decline in Alzheimer's disease.

What is the relationship between Aβ aggregation and tau protein?

Aβ aggregation can induce cellular changes that favor the aggregation of tau protein, contributing to neurodegeneration.

What are the roles of neurotrophic factors in Alzheimer's disease?

Neurotrophic factors may help strengthen synapses and promote neuronal survival, potentially counteracting the effects of Aβ.

What is the significance of the Congo Red stain in Alzheimer's research?

Congo Red is used to identify amyloid deposits, including senile plaques, in brain tissue.

What is the role of fibrillary astrocytes in Alzheimer's disease?

Fibrillary astrocytes are reactive glial cells that can contribute to the inflammatory response and neuronal damage in Alzheimer's disease.

What is the function of the amyloid intracellular domain (AICD)?

AICD is released into the cytoplasm after gamma-secretase cleavage and may have roles in gene transcription and cell signaling.

What is the significance of the transmembrane domain in APP processing?

The transmembrane domain is where gamma-secretase cleaves APP, influencing the production of amyloidogenic fragments.

What is the role of small molecule beta-breakers in Alzheimer's therapy?

Small molecule beta-breakers aim to reduce the formation of toxic Aβ aggregates in Alzheimer's disease.