SUMMARY
Alzheimer’s disease (AD) affects over 50 million people worldwide. The vast majority of patients, AD
develops sporadically in the absence of any known etiology other than advanced age. Despite the fact that AD
has been studied for over a century, its pathogenesis is still not completely understood, and drugs that could
stop or reverse the disease progression are not yet available. Similar to the age-dependent incidence of many
cancers, AD onset is believed to be caused by multiple hits of environmental, genomic, and aging-related
factors. To better understand the cellular and molecular interactions between human aging and AD
pathogenesis, induced neurons (iNs) directly converted from AD patient fibroblasts offer unique possibilities to
model and study the disease in a human age-equivalent neuronal model.
The teams around Dr. Gage and Dr. Mertens have recently shown that direct conversion of human AD
patient-derived fibroblasts into induced neurons (iNs) preserves signatures of cell aging and sporadic AD and
allows for the detection of cellular pathologies and disease drivers. Neuronal hypo-maturity represents a
fundamental AD-related cellular state in iNs, and the cancer-associated Pyruvate Kinase M2 (PKM2) splice
variant emerged as a key player that compromises mature neuronal metabolism and neuronal identity. PKM2
promotes neuronal vulnerability and de-differentiation via metabolic changes in the cytoplasm, and via
epigenetic processes in the nucleus, but the relative contribution of the two mechanisms remains elusive and
might differ substantially between cancer cells and post-mitotic neurons. To understand PKM2 in AD, and to
develop PKM-directed therapeutics, more knowledge regarding (1) the relationship between neuronal PKM2
and hallmarks of AD in the human brain, (2) the fundamental cell biological functions of PKM2 in aged human
neurons, and (3) the crosstalk between PKM-compromised neurons and their glial environment is needed.
This project will challenge the importance of shared pathogenic pathways between cancer and AD, and
assess age-dependently compromised neurons in the context of AD. First, the team will study the relationship
between cancer-related PKM2-positive neurons and AD pathology in the post-mortem human brain. Second,
the mechanistic impact of PKM2 imbalance on the metabolic state and neuronal fate stability of patient-specific
iNs will be assessed by transgene- and genome editing-based approaches. Third, pharmacological
compounds from the cancer field as a basis for developing PKM2-targeted therapeutics for AD will be
leveraged. Fourth, using a novel human iN-based three-dimensional multicellular model, the team will study
neuron-astrocyte coupling in the context of metabolically challenged iNs and their metabolic crosstalk with
human astrocytes. The ultimate goals of these four aims are to gain insight into the roles of the well-
established cancer protein PKM2 in age-related neurodegeneration and to exploit this knowledge to develop
therapeutic strategies against AD.