About

Ammasi Periasamy is a Professor of Biology and Biomedical Engineering at the University of Virginia, serving as the Center Director for the W.M. Keck Center for Cellular Imaging. His educational background includes a B.S. in Physics from the University of Madras, India, an M.S. in Physics with a focus on optics and spectroscopy from Annamalai University, and advanced degrees in Bioengineering from the Indian Institute of Technology, Madras. He also completed a postdoctoral fellowship in Bioengineering at the University of Washington, Seattle. Dr. Periasamy is an internationally recognized expert in advanced light microscopy techniques, with a particular focus on molecular imaging in living cells, tissues, and animals. His research emphasizes the design and development of optical methodologies, including advanced light microscopy techniques, to investigate and monitor protein-protein interactions, intravital imaging, and the physical parameters of normal versus cancer cells and tissues. He is a pioneer in the development of fluorescence lifetime imaging microscopy (FLIM) for measuring oscillations in cytosolic and nuclear free calcium in single intact living cells. Additionally, he has developed multi-color confocal, multiphoton, and FLIM-based Förster resonance energy transfer (FRET) imaging systems for protein localization in living specimens.

Research topics

• Cell biology
• Endocrinology
• Biochemistry
• Biology

Selected publications

• Welcome to PhotoniX Life: A new home for high-impact biophotonics research

  PhotoniX Life · 2026-01-01

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Early disruption of mitochondrial response to nutrients is a common feature in Alzheimer's disease

  Alzheimer s & Dementia · 2025-12-01

  articleOpen access

  BACKGROUND: Mitochondrial dysfunction, oxidative stress and mTOR dysregulation are defining features of Alzheimer's disease (AD). We discovered 'Nutrient-induced Mitochondrial Activity' (NiMA), an inter-organelle signaling pathway whereby insulin stimulation of lysosomal mTORC1 regulates mitochondrial activity and mtDNA synthesis in neurons in culture. We also reported NiMA to be downregulated by extracellular amyloid-β oligomers (AβOs) in neuron cultures (DOI: 10.15252/embj.2018100241.) The mechanism involves AβO-induced activation of mTORC1 at the neuronal plasma membrane (DOI: 10.1016/j.jalz.2016.08.015) and upregulation of superoxide dismutase 1 (SOD1), a major regulator of cellular redox (DOI: 10.1016/j.nbd.2022.105737). These observations raise the possibility that AβOs and AD risk factors known to inhibit insulin signaling disrupt NiMA at presymptomatic stages of AD. Here, we report that AβOs and APOE4 expression disrupt NiMA at presymptomatic AD stages and describe molecular mechanisms that are involved. METHOD: Live mitochondrial metabolism in brains of APP knock-in (APPKI) mice harboring Swedish, Arctic and Austrian mutations, and of APOE4 knock-in (APOE4KI) and APOE 3 (APOE3KI) mice were recorded with two-photon fluorescence lifetime imaging. RESULT: We found NiMA to be downregulated in 4-month-old APPKI mice and completely blocked in 6-month-old animals. Disruption of NiMA, thus occurs ∼2-3 months before microgliosis, cognitive decline and other pathological AD features detected in this Aβ mouse model. Mechanistically, we found that GSK3β signals through mTORC1 to regulate SOD1 and mitochondrial activity. Pharmacological inhibition of GSK3β in 4-month-old APPKI mice partially restored mitochondrial functioning, suggesting that GSK3β-mediated regulation of NiMA controls SOD1 interaction with cytosolic regulators. BioID, a proximity-dependent method for identifying protein-protein interactions in living cells, identified 10 potential novel regulators of NiMA. Additionally, NiMA was downregulated in 2 month old APOE4 KI mice. The latter result represents the earliest molecular dysfunction reported for APOE4 expression in mice. Thus, we are unveiling a fundamental mechanism connecting nutrient sensing, mTORC1 kinase activity and cytosolic redox to mitochondrial functioning in neurons. CONCLUSION: Our results indicate that NiMA disruption is an early event in AD pathogenesis.

  PublisherOA PDFDOI

• A UNIFIED MICROFLUIDIC PLATFORM FOR MECHANICAL STRESS-INDUCED BIOACCUMULATION IN DIVERSE MICROALGAE

  2025-10-20

  articleOpen access

  This paper presents a versatile microfluidic platform designed to systematically evaluate the effects of mechanical stress on multiple microalgal species.The platform enables precise, species-specific modulation of mechanical stress conditions in a high-throughput format.

  PublisherDOI

• Investigations on mitochondrial energy metabolism in prostate cancer by multiphoton FLIM

  2025-03-19

  articleSenior author
  PublisherDOI

• Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAA knock‐in mouse model of Alzheimer's disease

  Alzheimer s & Dementia · 2024-08-22 · 7 citations

  articleOpen access

  Abstract INTRODUCTION Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well‐known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient‐induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. METHODS Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock‐in (APP SAA ) mice using two‐photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. RESULTS NiMA is inhibited in APP SAA mice before other defects are detected in these Aβ‐producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APP SAA mice. DISCUSSION NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APP SAA mice, and may represent an early stage in human AD. Highlights Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient‐induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock‐in (APP SAA/+ ) mice. NiMA is disrupted long before learning and memory deficits in APP SAA/+ mice. Pharmacological interventions can rescue AD‐related NiMA disruption in vivo.

  PublisherOA PDFDOI

• Measuring Metabolic Changes in Cancer Cells Using Two‐Photon Fluorescence Lifetime Imaging Microscopy and Machine‐Learning Analysis

  Journal of Biophotonics · 2024-11-25 · 5 citations

  articleOpen accessSenior authorCorresponding

  ABSTRACT Two‐photon (2P) fluorescence lifetime imaging microscopy (FLIM) was used to track cellular metabolism with drug treatment of auto‐fluorescent coenzymes NAD(P)H and FAD in living cancer cells. Simultaneous excitation at 800 nm of both coenzymes was compared with traditional sequential 740/890 nm plus another alternative of 740/800 nm, before and after adding doxorubicin in an imaging time course. Changes of redox states at single cell resolution were compared by three analysis methods: our recently introduced fluorescence lifetime redox ratio (FLIRR: NAD(P)H‐ a 2 %/FAD‐ a 1 %), machine‐learning (ML) algorithms using principal component (PCA) and non‐linear multi‐Feature autoencoder (AE) analysis. While all three led to similar biological conclusions (early drug response), the ML models provided statistically the most robust significant results. The advantage of the single 800 nm excitation of both coenzymes for metabolic imaging in above mentioned analysis is demonstrated.

  PublisherOA PDFDOI

• In vivo two-photon FLIM imaging to investigate metabolism in live animals

  2024-01-26

  articleSenior author

  The advances in the field of optics and laser technologies are helpful to visualize and investigate the metabolism in live animals. Fluorescence lifetime imaging (FLIM) is a non-invasive optical technique to measure the fluorescence lifetime of the fluorophore towards its applications where fluorescence intensity-based techniques do not provide sufficient and accurate information to discriminate auto-fluorescent species. In contrast to conventional single photon excitation, two-photon excitation improves the penetration depth with low scattering of the longer wavelength to examine thick biological samples. In this work, we explain our 2photon-FLIM methodology for imaging mouse brains via a cranial window to investigate the changes in the NAD(P)H bound coenzyme, in both wild type and Alzheimer disease (AD) animal models before and after stimulation with nutrients. Moreover, phasor plot analysis has been used for removing lower a₂(%) fraction from the metabolic trajectory.

  PublisherDOI

• Mitochondrial NADK2-dependent NADPH controls Tau oligomer uptake in human neurons

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-01 · 3 citations

  preprintOpen access

  Alterations in NADH and NADPH metabolism are associated with aging, cancer, and Alzheimer’s Disease. Using 2P-FLIM imaging of the mitochondrial NAD(P)H in live human neurons and PS19 mouse brains, we show that tau oligomers (TauO) upregulate the mitochondrial de novo NADPH synthesis through NADK2. This process controls LRP1-mediated internalization of TauO, setting a vicious cycle for further TauO internalization. Thus, mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity.

  PublisherOA PDFDOI

• Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP ^SAA knock-in mouse model of Alzheimer’s disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-02-04 · 3 citations

  preprintOpen access

  Abstract Introduction Reduced brain energy metabolism, mTOR dysregulation, and extracellular amyloid-β oligomer (xcAβO) buildup characterize AD; how they collectively promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit N utrient-induced M itochondrial A ctivity (NiMA) in cultured neurons. We now report NiMA disruption in vivo . Methods Brain energy metabolism and oxygen consumption were recorded in APP SAA/+ mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. Results NiMA is inhibited in APP SAA/+ mice before other defects are detected in these amyloid-β-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. GSK3β signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with lithium or TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APP SAA mice. Conclusion NiMA disruption in vivo occurs before histopathological changes and cognitive decline in APP SAA mice, and may represent an early stage in human AD.

  PublisherOA PDFDOI

• Optimizing machine learning hyperparameters in two-photon FLIM image analysis

  2023-01-27 · 1 citations

  articleSenior author

  Artificial intelligence (AI)/machine-learning (ML) algorithms have been heavily used in data processing in various biological and clinical applications. Sensitive biological signaling can be monitored using two-photon fluorescence lifetime imaging microscopy (FLIM). Lifetime fitting, processing, and analyzing FLIM data of biological specimens can be a challenging and time-consuming affair. The recently developed Fluorescence Lifetime Redox Ratio (FLIRR) focuses on tracking metabolic changes ‘before-and-after-treatment’ in live cells using only two lifetime parameters. FLIM data produces many data parameters which are all associated with drug response in living cells. To predict drug cellular responses, we have chosen the Becker & Hickl SPCImage software to fit the lifetime images and the resultant data was used in ML analysis. With the objective of achieving even more robust statistical power predicting earliest drug effects, we developed Python software and autoencoder (AE) models to analyze the multiple biophysical FLIM parameters acquired in 2p-FLIM images of drug response in cervical cancer cells. The use of systematic hyperparameter (HP) tuning shows the variation in performance across the different models, enabling the selection of the highest performing model and HPs for repetition. Our results show that our optimized multi-parameter trained AE models can statistically outperform single FLIRR time-course analysis in discriminating earliest metabolic changes following drug treatment.

  PublisherDOI

Recent grants

• NIH Grant S10RR027409

  NIH · $347k · 2011

• NIH Grant S10RR025616

  NIH · $500k · 2010

• NIH Grant P01HL101871

  NIH · $16.7M · 2018

• NIH Grant S10OD016446

  NIH · $600k · 2014

• Dual-modal Microscopy of Metabolic Reprogramming in Cancer

  NIH · $412k · 2015–2017

Frequent coauthors

• Horst Wallrabe

  University of Virginia

  67 shared

• Masilamani Elangovan

  28 shared

• Yuansheng Sun

  28 shared

• Margarida Barroso

  Albany Medical Center Hospital

  22 shared

• Richard N. Day

  Indiana University School of Medicine

  21 shared

• Zdeněk Švindrych

  Dartmouth College

  19 shared

• Shagufta Rehman Alam

  University of Virginia

  17 shared

• Ruofan Cao

  University of Mississippi

  16 shared

Education

• Ph.D., Biomedical ENgineering

  Indian Institute of Technology Madras

  1983

• M.S., Biomedical ENgineering

  Indian Institute of Technology Madras

  1980

• M.S., Physics

  Annamalai University

  1974