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2024 Alzheimer's Association Research Fellowship (AARF)

In Vivo Roles of Rejuvenating Blood-Borne Factors in Amyloid-Beta Metabolism

How do proteins in the blood impact brain changes associated with aging and Alzheimer’s?

Alejandro Borja Grau Perales, Ph.D.
Icahn School of Medicine at Mount Sinai
New York, NY - United States


Aging is the biggest risk factor for Alzheimer’s. Studies indicate that levels of certain proteins in the blood can drive aging. Researchers have shown that proteins that decrease or increase with age in the blood may impact the onset and progression of Alzheimer’s.

Levels of a protein called TIMP2 decrease with age and are lower in individuals with Alzheimer’s. Recent studies have linked TIMP2 levels to changes in the extracellular matrix, the proteins between cells that protect and support them during aging. This was especially apparent in the hippocampus, a brain region involved in learning and memory and impacted early in Alzheimer’s. In aged mice, decreases in TIMP2 led to changes in the extracellular matrix in the brain that impaired brain cell health and function, while increasing TIMP2 levels reversed age-associated deficits in brain functioning. 

Dr. Alejandro Borja Grau-Perales and colleagues believe that TIMP2 may play an important role in the brain changes associated with Alzheimer’s, as well as in aging. TIMP2 inhibits the activity of a protein called MM2, which is involved in breaking down the extracellular matrix. In preliminary studies with genetically modified Alzheimer’s-like mice, the researchers found that TIMP2 levels regulated the accumulation of the protein fragment beta-amyloid (one of the hallmark brain changes associated with Alzheimer’s). Dr. Grau-Perales and team believe that restoring levels of TIMP2 in Alzheimer’s-like mice may reduce beta-amyloid accumulation by influencing the makeup of the extracellular matrix through interactions between TIMP2 and MMP2.

Research Plan

The research team will study the accumulation of beta-amyloid in genetically modified Alzheimer’s-like mice with and without TIMP2. They will investigate whether changes in beta-amyloid accumulation depend on the activity of MMP2 from astrocytes, helper cells in the brain. The researchers will then treat Alzheimer’s-like mice with TIMP2 to assess the impact on MMP2 activity and beta-amyloid accumulation.
Dr. Grau-Perales and colleagues will also use high-powered microscopes to examine the extracellular matrix in Alzheimer’s-like mice with and without TIMP2. They will study how TIMP2 may impact changes in the extracellular matrix that affect beta-amyloid accumulation in Alzheimer’s-like mice.


This study may contribute to our understanding of how rejuvenating proteins in the blood impact Alzheimer’s-associated brain changes. The results may support modulation of the extracellular matrix as a new therapeutic avenue to prevent or treat Alzheimer’s. 

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