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Molecular mechanisms of AD pathogenesis

Pathological manifestation of Alzheimer’s disease (AD) precedes more than a decade before the appearance of clinical symptoms (e.g., cognitive impairment). Comparative studies on cognition and the presence of blood, cerebrospinal fluid (CSF), and neuroimaging biomarkers have demonstrate a 10 to 20-year preclinical phase that precedes the manifestation of symptomatic AD. During this preclinical phase both intra- and extra-neuronal pathologies including β-amyloid (Aβ) plaques, neurofibrillary tangles, dystrophic neurites (DNs), mitochondrial degeneration, and glial activation (Fig. 1) advance the onset of clinical symptoms. Currently, there is no effective drug to prevent or cure AD. Large numbers of failed clinical trials and the complexity of disease mechanism suggest that AD diagnosis and disease modifying strategies need to be targeted at early pre-clinical stage. Hence, identifying early diagnosis biomarkers and understanding the cellular/molecular mechanism of etiopathophysiology are prerequisite for effective AD drug development.


The cellular homeostasis relies on spontaneous degradation of its undesired components through autophagy and endo-lysosomal pathways; both processes ultimately are targeted to the lysosomes. Increasing evidence suggests that autophagy-lysosomal dysfunctions contribute to the initiation and progression of AD by disrupting the degradation of toxic molecules such as Aβ and tau. We reported that accumulation of dysfunctional lysosomes and ER-mitochondria inclusion in Aβ core surrounding DNs occurs during Aβ plaque initiation in AD brains. The accumulation of cellular organelles and proteins in DN is a distinguishing feature in AD brains because diffused Aβ plaques those devoid of such DN formation are commonly found in non-demented elderly brain.


Our long-term research goal is to determine novel pathways that are associated with neuronal/glial homeostatic dysfunction in AD and to target DN forming organelles/proteins (Fig. 1) for developing early AD diagnostic biomarkers and delivering Aβ targeted drugs by focusing on specific areas of research.

Alzheimer's research

Fig 1. A neuritic plaque in AD brain is composed with an Aβ-deposited core that is surrounded by dysfunctional organelles /proteins accumulated DNs and activated glial cells. Our research focuses to understand organelle dysfunction mechanism during plaque initiation and to utilize accumulated organelles in DNs for identifying early diagnostic biomarkers and delivering Aβ-targeted drugs.

Areas of Research

Additional Resources