Preclinical Insights Into CD4+ CAR-T Targeting Amyloid Beta in Alzheimer's Disease

A recent preclinical study used CD4+ CAR‑T cells engineered to recognize fibrillar amyloid‑β (Aβ) plaques, evaluated in the 5xFAD mouse model of rapid amyloid accumulation.

The researchers describe a comparison of stable retroviral transduction versus transient mRNA nucleofection followed by amyloid and neuroimmune readouts. Reported outcomes differed by approach, with separate patterns described in meningeal (dural) versus brain parenchymal compartments.

The engineered receptor used a lecanemab-derived targeting head in a construct referred to as Lec28z, expressed in CD4+ T cells. In activation assays, this CAR responded selectively to fibrillar Aβ while remaining inactive in the presence of monomeric Aβ, with one statistical value reported for this selectivity (p < 0.0001).

For the stable retroviral transduction arm, stably engineered CAR‑T cells significantly reduced dura amyloidosis (p = 0.0151). In the same set of results, this stable approach did not significantly reduce parenchymal plaques, drawing a spatial distinction between meningeal and parenchymal amyloid readouts. Alongside the amyloid observations, there were also increases in microglial activation markers in this condition.

In contrast, the transient mRNA nucleofection arm showed significant reductions in parenchymal plaque metrics, including Aβ coverage (p = 0.0127) and methoxy-stained dense cores (p = 0.0339). There were reductions in glial coverage measures labeled as microgliosis and astrogliosis, specifically Iba1 coverage (p = 0.0220) and GFAP coverage (p = 0.0055).