Rudolph E. Tanzi

In 1987, based on his doctoral studies at Harvard Medical School, he was the lead author of seven papers published in Science and Nature between 1987 and 1988, describing the initial cloning, mapping, and characterization of the gene encoding the amyloid beta-protein precursor (APP).

All three genes remain among the most highly studied drug targets in the field of AD, especially about therapeutic strategies aimed at reducing beta-amyloid deposition.

Importantly, they showed CD33 inhibits microglial phagocytosis and clearance of Abeta and induces pro-inflammatory cytokine release leading to neuroinflammation.

CD33 has now emerged as the primary target for novel drug discovery programs aimed at curbing neuroinflammation, at over a dozen pharmaceutical and biotech companies.

Beginning in 1994, in a study published in Science with his post-doctoral fellow Ashley Bush, Tanzi demonstrated a key role for zinc, copper, and iron in beta-amyloid deposition and Lewy body formation.

Also in 2000, Tanzi collaborated with cell biologist, Dora Kovacs, to show that blocking the enzyme acetyl-coA acetyltransferase 1 (ACAT1), responsible for storing cholesterol as lipid droplets in intracellular rafts, prevents the generation of Abeta.

Most recently, this led to their discovery that ACAT1 promotes the palmitoylation of APP dimers in lipid rafts, rendering them more susceptible to beta-secretase cleavage and Abeta production.

In 2005, Tanzi and his ex-trainee and late colleague, Robert Moir, reported in the Journal of Biological Chemistry the existence of auto-antibodies against oligomeric Abeta, which they showed to protect against risk for AD.

This discovery inspired Roger Nitsch and the Swiss biotech, Neurimmune to develop an AD therapy based on isolating those auto-antibodies from memory B-cells and reverse translating them into the promising beta-amyloid immunotherapy, aducanumab.

These include ALZT-OP1 (AZTherapies) targeting microglial activation and neuroinflammation, and a neuroprotective drug combination, called AMX0035 (Amylyx, co-founded by Josh Cohen, Justin Klee with Tanzi serving as the founding chair of the Scientific Advisory Board).

In another set of groundbreaking studies, Tanzi, working with Robert Moir, investigated whether amyloid beta (Abeta) may play a normal role in the brain.

These findings suggest that even subclinical levels of bacteria, viruses, or other microbes, entering or activating the brain, may initially trigger plaque formation and start the amyloid cascade rolling.

Tanzi is currently carrying out large-scale metagenomic sequencing of post-mortem AD brains, to catalog the microbes that may be initiating amyloid pathology.

In other studies, Tanzi and his trainee, Zhongcong Xie, published several seminal papers providing the first evidence that the widely used general inhalant anesthetic, isoflurane, induces Abeta generation, apoptosis, and neurodegeneration in the mouse brain and post-operative CSF of patients.

With trainee, Lee Goldstein, Tanzi showed how head injury due to a bomb blast or collision causes rapid induction of tangles and gliosis in mice.

Now referred to as the “bobblehead” effect, it has been postulated to be the main cause of the subsequent onset of chronic traumatic encephalopathy in human subjects exposed to repeated concussion and head trauma.

Tanzi serves on dozens of editorial and scientific advisory boards and as chair of the Cure Alzheimer's Fund Research Leadership Group.