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Lei Liu, MD, PhD

BWH Job Title:

Lead Investigator

Academic Rank:

Assistant Professor




Lei Liu

Unveiling γ-secretase Abnormality: Unraveling the Fundamental Pathophysiology of Alzheimer's Disease


The γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). PSEN1 forms the catalytic core of the γ-secretase complex and thereby directly mediates the stepwise hydrolysis of the APP transmembrane domain, yielding Aβ peptides with different C-terminal lengths, ranging from 37 to 49. In terms of PSEN1 enzymology, higher production of longer Aβ indicates a deficiency of enzymatic processivity. The longer the peptide goes, the more hydrophobic transmembrane region of APP retains in the Aβ peptide. From both familial and sporadic AD patients’ brains, we have consistently observed the deposition of longer, aggregation-prone Aβ peptides, such as any peptide species longer than 42 residues.

Physiologically, 10% of all Aβ produced by wild-type human PSEN1 is aggregation-prone species, which suggests an under optimal enzymatic processivity. More than 300 missense AD-causative PSEN1 mutations could further exaggerate this enzymatic processivity deficit, increasing the aggregation-prone species production up to 50% of all Aβ produced. Meanwhile, multiple APP mutations could work through a similar mechanism to amplify the γ-secretase abnormality, increasing aggregation-prone species production to 70% of all Aβ produced. Through the last decade of research, we have identified the detailed mechanism of this innate enzymatic processivity deficit with wild-type PSEN1 and APP; and also, how this deficit gets amplified by disease-causing mutations. We first discovered PSEN1 and APP variants could overcome this innate enzymatic issue through enhancing the substrate (APP) and enzyme (PSEN1) biomolecular affinity. Later, we confirmed this mechanism shared with the effects of a class of promising small molecules, γ-secretase modulators (GSM). Next, we found the enzymatic processivity deficit of each AD-causative PSEN1 mutation accurately predicts the age of onset (AOOs) for familial autosomal dominant AD patients (ADAD). Further, we leverage the same system to functionally characterize APP processing by γ-secretase across a large set of PSEN1 pathogenic variants with AAOs ranging from the 20s to the 70s. We then found how this mutation-level characterization of γ-secretase function may explain heterogeneity in neuroimaging and biofluid biomarkers, as well as clinical measures among PSEN1 carriers with available data from the Dominantly Inherited Alzheimer’s Network Observational Study (DIAN-Obs).

From our decades-long scientific investigation, our main findings are the γ-secretase activity 1) is already optimal under physiological conditions; 2) is further impaired with PSEN1 mutations, in which the impairment correlates to the clinical phenotypes; 3) is also impaired as the aging process and AD brain pathology advance in the sporadic AD context; and 4) could be restored with artificial variants genetically or GSM pharmacologically. Currently, multiple pharmaceutical companies revive GSM programs in the light of anti-amyloid therapy successes, exemplified by the launch of Lecanemab. Here we are highlighting the γ-secretase abnormality as the fundamental pathophysiology of AD.

1. Nishimura, M. et al. Age-related modulation of γ-secretase activity in non-human primate brains. J Neurochem 123, 21-28 (2012).
2. Bhattarai, S., Liu, L. & Wolfe, M. S. Discovery of aryl aminothiazole γ-secretase modulators with novel effects on amyloid β-peptide production. Bioorg Med Chem Lett 54, 128446 (2021).
3. Liu, L., Lauro, B. M., Wolfe, M. S. & Selkoe, D. J. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. Journal of biological chemistry 296, (2021).
4. Stephanie, A. S. et al. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer’s disease. bioRxiv 2023.07.04.547688 (2023).
5. Liu, L. et al. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer’s disease. Alzheimers Dement 19, 79-96 (2023).
6. Schultz, S. A. et al. Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer’s disease. Aging Cell 22, e13871 (2023).