Christian Haass, Germany
University Metabolic BiochemistryAuthor Of 4 Presentations
LIVE DISCUSSION
THERAPEUTIC MODULATION OF MICROGLIA AND TREM2 FUNCTION AND DYSFUNCTION
THERAPEUTIC MODULATION OF TREM2 FUNCTION
Abstract
Abstract Body
Alzheimer’s disease (AD) is currently untreatable, and therapeutic strategies targeting the amyloid cascade have not yet been successful, indicating that novel treatment strategies are required. Recent genome wide association studies have identified a number of risk factors in genes expressed in microglia, including the Triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 is essential for the transition of homeostatic microglia to disease associated microglia. TREM2 loss of function locks microglia in a homeostatic state, and affects a multitude of microglia functions such as chemotaxis, phagocytosis, cell survival, lipid- and energy metabolism. Biomarker studies revealed that TREM2 may protect humans from AD. To enhance TREM2 activity, we selectively increased the full-length protein on the cell surface via reducing its proteolytic shedding by ADAM proteases. We generated a panel of monoclonal antibodies against the stalk region of TREM2, which encompasses the cleavage site, with the aim to compete for α-secretase mediated shedding. Monoclonal antibody 4D9, which binds to an epitope close to the ADAM10/17 cleavage site, stabilized TREM2 on the cell surface, reduced its shedding and concomitantly activated phospho-SYK signaling in a dose dependent manner. Moreover, 4D9 stimulated survival of cultured macrophages, increased myelin debris uptake of primary microglia and reduced the amyloid burden in a mouse model for AD pathology. Thus, our findings demonstrate that antibodies elevating full-length TREM2 on the cell surface allow selective modulation of TREM2 dependent functions in microglia and macrophages, which may be of potential therapeutic benefit.
THE CSF STREM2 INCREASE IS AMYLOID-Β DRIVEN AND ASSOCIATES WITH SLOWER AMYLOID-Β DEPOSITION AND CLINICAL DECLINE IN AUTOSOMAL-DOMINANT ALZHEIMER DISEASE
Abstract
Aims
Therapeutic modulation of microglial functions may provide an additional strategy to slow progression of Alzheimer disease (AD). Although animal models suggest that TREM2 function is protective, we do not know if that is the case in AD patients. We therefore studied the dynamics of soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) as a surrogate marker of TREM2 signalling and its relationship with AD evolution.
Methods
We measured sTREM2 in longitudinal CSF samples from 261 participants in the Dominantly Inherited Alzheimer Network (DIAN) study, including 161 mutation carriers (MC) and 100 non-carriers (NC). We assessed the association between the CSF sTREM2 dynamics and the longitudinal changes in amyloid-β (Aβ), tau and neuronal damage markers along with the cognitive decline (cognitive composite).
Results
Higher Aβ burden at baseline (lower CSF Aβ42) was associated with a higher subsequent rate of sTREM2 increase (β=-3.704x10-2, p=0.004) in MC. This increase was independent of tau-related pathology at baseline (CSF t-tau and p-tau). A higher rate of sTREM2 increase was associated with slower Aβ deposition either measured by CSF Aβ42 (r=0.56, p=0.01, presymptomatic MC) or PIB-PET (r=-0.38, p=0.05, all MC). Furthermore, higher sTREM2/p-tau at baseline predicted slower hippocampal volume and precuneus cortical shrinkage (β=1716.05, p=0.004; β=2.032x10-2, p=0.03, respectively). Strikingly, we found a strong association between higher rate of sTREM2 increase and slower cognitive decline (r=0.62, p=0.003) in presymptomatic MC.
Conclusions
CSF sTREM2 increase in autosomal-dominant AD is mainly driven by Aβ accumulation. Increased TREM2 expression and signalling appears to protect against Aβ deposition and cognitive decline.
Presenter of 3 Presentations
LIVE DISCUSSION
THERAPEUTIC MODULATION OF TREM2 FUNCTION
Abstract
Abstract Body
Alzheimer’s disease (AD) is currently untreatable, and therapeutic strategies targeting the amyloid cascade have not yet been successful, indicating that novel treatment strategies are required. Recent genome wide association studies have identified a number of risk factors in genes expressed in microglia, including the Triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 is essential for the transition of homeostatic microglia to disease associated microglia. TREM2 loss of function locks microglia in a homeostatic state, and affects a multitude of microglia functions such as chemotaxis, phagocytosis, cell survival, lipid- and energy metabolism. Biomarker studies revealed that TREM2 may protect humans from AD. To enhance TREM2 activity, we selectively increased the full-length protein on the cell surface via reducing its proteolytic shedding by ADAM proteases. We generated a panel of monoclonal antibodies against the stalk region of TREM2, which encompasses the cleavage site, with the aim to compete for α-secretase mediated shedding. Monoclonal antibody 4D9, which binds to an epitope close to the ADAM10/17 cleavage site, stabilized TREM2 on the cell surface, reduced its shedding and concomitantly activated phospho-SYK signaling in a dose dependent manner. Moreover, 4D9 stimulated survival of cultured macrophages, increased myelin debris uptake of primary microglia and reduced the amyloid burden in a mouse model for AD pathology. Thus, our findings demonstrate that antibodies elevating full-length TREM2 on the cell surface allow selective modulation of TREM2 dependent functions in microglia and macrophages, which may be of potential therapeutic benefit.
THERAPEUTIC MODULATION OF MICROGLIA AND TREM2 FUNCTION AND DYSFUNCTION
Moderator of 1 Session