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). During this pre-clinical phase both intra and extra-neuronal pathologies including β-amyloid (Aβ) plaques, neurofibrillary tangles, dystrophic neurites (DNs) formation, mitochondrial degeneration, and glial dysfunction advance AD progression to the clinical phase (Fig. 1). Currently, there is no effective drug to prevent or cure AD. Large number of clinical trials fails 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 etiopathphysiology 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 occur during Aβ plaque initiation in AD brains. Although, Aβ deposition commonly found in non-demented elderly brain, the accumulation of cellular organelles and proteins in DN is a distinguishing feature in AD brains.

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

Fig 1. We focus on the AD pathogenic mechanism to develop early diagnostic biomarkers and identify therapeutic treatments by focusing on cellular homoeostatic defect that initiate/elevate Aβ deposition, and DNs forming proteins and organelles.

Areas of Research

Dysfunctional lysosomal clustering

Lysosomal clustering in AD brain-therapeutic intervention and diagnostic potential

The accumulation of diversified proteins and organelles in DN surrounding amyloid plaques correlate with the dysfunction of various neuronal processes during AD progression. We have shown that hydrolase deficient, but saposin enriched, lysosomes are massively clustered in DNs during neuritic plaque formation in AD brain. Our current studies aim to determine whether:

a prosaposin/saposin-mediated pathway plays a key role in lysosomal dysfunction in AD.
clustered lysosomes in AD brain and lysosomal proteins in bio-fluids can be used as AD diagnostic biomarkers.
lysosomal accumulation can be targeted for AD drug development.

Fig: Saposin (SAP)-C and its precursor prosaposin (PSAP) accumulate around thioflavin-S (Thi-S) labeled Aβ-plaque in APP knock-in (APPNL-G-F), 5xFAD, and APP-PS1delE9 (PA) mouse brains.

Mitochondrial dysfunction in AD brain

Efficient trafficking and clearance of aged mitochondria in neurons is critical for providing energy during synaptic activity. We found that mitochondrial density is increased at the synaptic site, which is likely to provide sufficient energy for the synapse. However, to continue the required energy delivery, aged mitochondria need to be transported back to the neuronal soma for clearance via mitophagy. We report that axonal mitochondria are trapped and degenerated in a tubular endoplasmic reticulum (ER) clustered area of AD brain. A dynactin pointed end subunit, ACTR10, mediate retrograde trafficking of mitochondria in neurons, while Nipsnap1, a mitochondrial matrix protein facilitates mitophagy by accumulating on the mitochondrial surface upon depolarization of mitochondria. Our research aims to elucidate the role of Nipsnap1 and ACTR10 in mitochondrial degeneration in AD.

Fig: Distribution of mitochondria in an axon participating in synapsis was reconstructed from a series of 3-dimentional electron microscopy (3D-EM) images obtained from a 6-month-old wild type mouse brain. Mitochondria were clustered at the synaptic site in the axon.

Utilizing bio-fluid based Aβ seed extension for noninvasive AD diagnosis

The presence of higher level of plasma matrix proteins such as albumin alpha2-macroglobulin, lipoprotein, etc., hinders the accuracy of immunoassays to detect the amount of Aβ in serum/plasma samples. Evidence suggests that plasma Aβ42 and Aβ40 levels are associated with the levels of CSF Aβ42/Aβ40 and cerebral amyloid deposition. Regardless of the amount of monomeric Aβ42 or Aβ40, we aim to determine the potential Aβ aggregates in serum using seed extension methods to diagnose AD using noninvasive methods.

Fig: Aβ aggregation progresses via two steps, nucleation and fibril extension. During nucleation, smaller aggregates are formed by assembly of multiple monomeric species. During the extension phase, monomers are attached to existing oligomers that extend the fibrils. The nucleation (seed formation/lag) phase can be omitted by adding preformed oligomers/fibrils/seeds in the reaction mixture.

Additional Resources

Featured Publications

View a complete list of research studies led by Dr. Golam Sharoar.

Md. Golam Sharoar, John Zou, Marc Benoit, Wanxia He and Riqiang Yan. DCTN6 deficiency enhanced aging associated dystrophic neurites formation in mouse brains. Neurobiology of Aging, 107: 21-29; Nonmember, 2021. (Corresponding author). doi.org/10.1016/j.neurobiolaging.
2021.07.006.
Md Golam Sharoar, Sarah Palko, Yingying Ge, Takaomi C Saido and Riqiang Yan. Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer’s disease brains. Molecular Neurodegeneration, 16(1):45; Jul 2021. doi: 10.1186/s13024-021-00464-1.
Md Golam Sharoar, Xiangyou Hu, Xin-Ming Ma, Xiongwei Zhu and Riqiang Yan. Sequential formation of different layers of dystrophic neurites in Alzheimer’s disease brains. Molecular Psychiatry, 24(9):1369-1382; Sep 2019. doi: 10.1038/s41380-019-0396-2. Featured figure: Dystrophic neurites labeled by pre-autophagosomal proteins in Alzheimer's brains. Molecular Psychiatry, 24(9):1247; Sep 2019. doi: 10.1038/s41380-019-0476-3.
Md. Golam Sharoar, Qi Shi, Yingying Ge, Wanxia He, Xiangyou Hu, George Perry, Xiongwei Zhu and Riqiang Yan. Dysfunctional tubular endoplasmic reticulum induces formation of dystrophic neurites in Alzheimer’s disease. Molecular Psychiatry, 21:1263-1271; Sep 2016. doi: 10.1038/mp.2015.181.
Md. Golam Sharoar, ArjunThapa, Md. Shahnawaz, Vijay Samkar Ramasamy, Eun-Rhan Woo, Song Yub Shin & Il-Seon Park. Keampferol-3-O-rhamnoside abrogates amyloid beta toxicity by modulating monomers and remodeling oligomers and fibrils to non-toxic aggregates. Journal of Biomedical Science, 19:104; Dec 2012. doi: 10.1186/1423-0127-19-104 (Corresponding author).

Lab Members

Md Golam Sharoar, PhD
Assistant Professor, Internal Medicine & Alzheimer’s Disease Research Program

Zakia Zaman
Research Assistant