About the Genetics and Aging Research Unit

The Genetics and Aging Research Unit at Massachusetts General Hospital is a collaborative effort of multiple laboratories dedicated to discovering molecular mechanisms of pathology and developing therapies for treating and preventing Alzheimer’s disease.

The Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) was founded by Dr. Rudy Tanzi in 1995. Under his directorship, the unit now consists of nine laboratories focusing on:

1. Identifying genetic risk factors for Alzheimer's disease as director of the Cure Alzheimer’s Fund-Alzheimer’s Genome Project elucidating the mechanisms underlying the etiology and pathogenicity of the genes responsible for Alzheimer's disease through the application of molecular, cell biological, and biochemical strategies
2. Developing 3D cultures, brain organoids, and animal models of neurodegenerative diseases
3. Carrying out drug discovery and development for novel therapies aimed at treating or preventing Alzheimer's disease.

The ongoing research in the unit follows a basic roadmap that includes disease gene discovery, translational and functional studies to identify pathogenic gene variants and mutations, molecular biological and biochemical studies to elucidate pathways that have been impacted by disease-associated gene changes, and novel drug screening assays to identify small molecules or supplements that can halt or reverse pathogenic molecular and biochemical phenotypes at the cellular level.

Mission

The mission of the Genetics and Aging Research Unit is to someday end the scourge of Alzheimer’s and other neurodegenerative diseases by employing a strategy of early prediction and detection of disease and early prevention and intervention.

Milestones

Summary of Key Discoveries of the Genetics and Aging Research Unit

1980-1989

• 1984-1988: Was among the first to discover the amyloid precursor protein (APP) gene and map it to chromosome 21, for which he produced the first complete link age map and used it first show genetic linkage of Alzheimer's disease (AD) to chromosome 21.

1990-1999

• 1993: Carried out chromosome 21 physical mapping leading to first familial ALS gene-SOD1.
• 1993: Discovered the Wilson's disease gene and mutations causing the neurodegenerative disorder caused by copper toxicity.
• 1993: Carried out physical mapping of chromosome 21 to reveal SOD1 as the first gene causing familial amyotrophic lateral sclerosis (with Dr. Bob Brown).
• 1994: Showed zinc/copper drives Aβ aggregation and neurotoxicity.
• 1995: Cloned and discovered first mutations in AD gene presenilin 2; collaborated on the cloning of the AD gene, presenilin 1.
• 1998: Showed alpha-2 macroglobulin (A2M) is an AD susceptibility gene.
• 1999: Mapped the BACE2 gene to the obligate Down Syndrome region of chromosome 21

2000-2009

• 2000: Discovered genetic linkage of AD to chromosome 10, implicating the gene encoding the insulin-degrading enzyme.
• 2001: Showed that AD pathology in transgenic mice could be ameliorated by a zinc-copper chelator, clioquinol (PBT1)
• 2003: Clioquinol (PBT1) was successful in a phase 2 AD clinical trial.
• 2003: Discovered that apoptosis and caspase activation induces beta-amyloid deposition.
• 2005: Discovered ubiquitin 1 to be an AD gene.
• 2005: Showed auto-antibodies to oligomeric Aβ protect against AD–acknowledged to have significantly influenced the promising AD immunotherapy, Aducanumab.
• 2007: Established widely used gene databases: AlzGene, PDGene and SZGene.
• 2008: Employed family-based GWAS to discover the AD gene, CD33, the first AD gene controlling neuroinflammation and innate immunity in the brain, now a major drug target for AD.
• 2008: Showed first evidence that isoflurane (a general anesthetic) induces Aβ generation and neurodegeneration, leading to a dramatic reduction in its clinical use.

2010-2019

• 2010: Zinc-copper chelator, PBT2 (from Prana Biotechnology, now Alterity Therapeutics) successful in a phase 2 AD clinical trial.
• 2010: Discovered the first non-NSAID class of gamma secretase modulators (GSM), which selectively lower production of Aβ42 without off-target effects of gamma secretase inhibitors. A clinical candidate is slated for phase I clinical trials in 2021.
• 2010: Discovered and validated the first highly penetrant late-onset AD mutations in ADAM10, the main alpha-secretase that precludes Aβ production in the brain.
• 2010: Demonstrated Aβ to be a potent antimicrobial peptide in the brain's innate immune system.
• 2012: With Lee Goldstein, first showed that the “bobble head” effect of head injury/concussion causes tangle and gliosis pathology leading to chronic traumatic encephalopathy.
• 2013: Showed that CD33 controls neuroinflammation in AD at the microglial level.
• 2014: Invented a 3D human stem cell-derived neural culture AD model that recapitulated plaques and tangles in vitro for the first time. This was the first model to definitively show that β-amyloid plaques induce bona fide neurofibrillary tangles from endogenous tau.
• 2016: Demonstrated Aβ to be a potent antimicrobial peptide in the brain; showed for the first time in mice and 3D models that microbes can rapidly (overnight) seed deposition of β-amyloid as a defense mechanism of the brain's innate immune system.
• 2018: Invented a 3D human stem cell-derived mixed neural-astrocyte-microglial microfluidic AD mode l, which showed neuronal Aβ deposition/tangle formation induces microglial activation and synaptic pruning/axotomy beginning with the astrocytic release of MCP1.
• 2018: Showed that the amyloid beta protein protects the brain against herpes virus infection.
• 2018: Demonstrated the key role of exercise-induced hippocampal neurogenesis in ameliorating AD pathology in AD transgenic mice and successfully mimicked this effect pharmacologically and genetically.
• 2019: Demonstrated that ataxin-1, the gene causing spinal cerebellar ataxia, regulates the production of amyloid beta by controlling the expression of the BACE1 gene.

2020-Present

• 2020: Used multiple whole genome sequencing datasets for the first time to identify sex-specific genetic risk factors for AD (ZBTB7C, GRID1, RIOK3, MCPH1) as well as several novel Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development (FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, CLSTN2, DTNB, DLG2).
• 2021: Showed astrocytic interleukin-3 programs microglia and reduces neuroinflammation in Alzheimer's disease. Co-authored successful clinical trial in ALS leading to approval of Relyvrio (Amylyx).
• 2022: Used whole-genome sequencing to discover two new genes associated with Alzheimer's disease: DTNB and DLG2. Discovered that the plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults.
• 2023: Developed a 3D model of AD incorporating peripheral immune cells to reveal the role of brain-infiltrating T cells in AD pathogenesis.
• 2023: Demonstrated how the exercise-induced muscle hormone, irisin, triggers enzymatic breakdown of β-amyloid in the brain.
• 2023: Discovered the role of mast cells in driving neuroinflammation in AD.