Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Alzheimer's disease (AD) is the leading cause of dementia, characterized by amyloid-beta (Aβ) accumulation.
• Emerging therapies target Aβ, shifting focus from extracellular plaques to intracellular Aβ toxicity.

Purpose of the Study:

• To review current understanding of intracellular Aβ toxicity, particularly in lysosomes.
• To highlight emerging molecular pathways implicated in AD pathogenesis.
• To discuss potential next-generation therapeutic targets for Alzheimer's disease.

Main Methods:

• Literature review of recent studies on intracellular Aβ.
• Analysis of molecular mechanisms involving lysosomes, gangliosides, and complement cascade.
• Synthesis of current therapeutic developments and future directions.

Main Results:

• Intracellular Aβ accumulation in lysosomes is a critical driver of AD pathology.
• Lysosomal acidification, membrane integrity, and interactions with gangliosides are key determinants.
• The complement cascade and asparaginyl endopeptidase link Aβ to tau pathology and neurodegeneration.

Conclusions:

• Lysosomes are central to intracellular Aβ toxicity in Alzheimer's disease.
• Emerging pathways offer promising targets for novel AD treatments.
• Understanding these mechanisms is crucial for developing next-generation disease-modifying therapies.