Microglia (MG), the tissue resident immune cells of the central nervous system, are strongly implicated in Alzheimer disease (AD) pathogenesis and progression, yet whether they prevent or promote disease remains controversial. This question is of paramount clinical interest since monoclonal antibodies directed against amyloid beta (Aβ) are thought to stimulate microglial phagocytosis of Aβ plaques. Building on our previous work in engineering macrophages to express chimeric antigen receptors (CAR) for cancer cell phagocytosis, we sought to design microglia capable of engulfing misfolded proteins. We hypothesized that replacing endogenous microglia with Aβ targeting CAR-expressing myeloid surrogates into the brains of AD mice would modulate Aβ pathology, shed light on MG’s role in AD, and inform the development of future cell engineering approaches for combating neurodegenerative proteinopathies. In both human and murine cells, we showed in vitro that expression of an anti-Aβ CAR led to efficient engulfment and breakdown of Aβ aggregates. Remarkably, in a genetically engineered mouse model of AD we discovered that engraftment of CAR-expressing myeloid cells led to a detrimental exacerbation of Aβ plaque pathology. This unexpected finding not only provides evidence that neurodegenerative pathology can be influenced by replacing endogenous microglia with donor surrogates, but also underscores the necessity for further research into the impact of microglial phagocytosis on AD and the continued refinement of cell-based immunotherapies for treating neurodegenerative disorders. In pursuit of this goal, the latter portion of this thesis delves into engineering microglia to target other neurological co-pathologies observed in AD, such as tau and α-synuclein, and investigates alternative methods for generating CAR-microglia in vivo using nonviral approaches. Collectively, this work presents a novel cellular therapy-based framework for addressing neurodegenerative proteinopathies.