Roberto Malinow, M.D., Ph.D.

Professor, Section of Neurobiology, UCSD,
Professor of Neurosciences, UCSD
Shiley Chair in Alzheimer’s Disease Research in Honor of Dr. Leon Thal

Dr. Malinow’s research is directed toward understanding how the brain forms and stores memories. His laboratory examines how neuronal activity controls the strength of communication between neurons, at sites called synapses. Synapses are key sites affected by diseases of cognition. Synaptic plasticity, or the ability of the connection between neurons to vary, is thought to underlie the formation and storage of memories. It is thought that a detailed understanding of synaptic plasticity will identify critical steps that may be the targets of diseases such as Alzheimer’s disease. Such an understanding eventually may lead to treatments that prevent the disease.

Funded Research

Project Description Researchers Funding
Normalizing Abeta synaptic depression with drugs targeting PICK1

There is general agreement that beta amyloid (Aβ) is a likely causative agent in the development of Alzheimer’s disease. There is growing evidence that early in the disease an important target of Aβ is the synapse, the site of communication between neurons. We have found that exposure of synapses to Aβ causes their weakening. In this proposal we will examine the role played by PICK1, a protein that associates with synaptic receptors and participates in the weakening of synapses by Aβ.

NMDA Receptors

The traditional signaling induced by NMDA-Rs is triggered by the Ca2+ ions that pass through the NMDA-R channel. However, preliminary data indicate that blockers at the NR2B subunit, but not the NR1 subunit or the channel of the NMDA receptor, prevent the synaptic effects of the NMDA receptor. These findings suggest that Abeta employs novel, non-ion flux NMDA-R signaling mechanisms to produce synaptic depression. These results may open up a new group of potential therapeutic targets for treatment of Alzheimer’s disease.

Rescue of Synapses in AD Rodent Models

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer’s disease (AD). In our previous studies, we have shown that amyloid beta (Aβ), a peptide implicated in the pathogenesis of AD, is secreted in an activity-modulated manner. Furthermore, we found that secreted Aβ leads to loss of synaptic receptors (by endocytosis), synaptic depression and removal of dendritic spines, sites of excitatory synaptic transmission. We now wish to understand the following: Can synaptic loss seen in AD transgenic animals be rescued by block of synaptic receptor endocytosis?

Understanding the Cell Biology Underlying the Effects of Abeta on Synapse

This research will attempt to understand the following central cell biological questions:


Selected Publications

These published papers resulted from Cure Alzheimer’s Fund support.

Miyazaki T, Takase K, Nakajima W, Tada H, Ohya D, Sano A, Goto T, Hirase H, Malinow R, Takahashi T, Disrupted cortical function underlies behavior dysfunction due to social isolation, J Clin Invest., 122(7), Jul 2, 2012, 2690-701
Wu-Zhang AX, Schramm CL, Nabavi S, Malinow R, Newton AC, Cellular pharmacology of protein kinase Mζ (PKMζ) contrasts with its in vitro profile: implications for PKMζ as a mediator of memory, J Biol Chem., 287(16), Apr 13, 2012, 12879-85
Kessels HW, Nguyen LN, Nabavi S, Malinow R, The prion protein as a receptor for beta-amyloid, Nature, 466(7308), Aug 12, 2010, E3-E5
Wei W, Nguyen L, Kessels HW, Hagiwara H, Sisodia S, Malinow R, Amyloid beta from axons and dendrites reduces local spine number and plasticity, Nature Neuroscience, 13(2), Feb 2010, 190-196