Early synaptic endosome dysfunction in Alzheimer disease: convergence of ApoE, Aβ & tau

Alzheimer disease (AD) is a heterogenous disease of aging brain with diverse influences including alterations in lipid, immune and protein degradative function.

Our group contributed to discoveries showing that 3 proteins/peptides linked to AD: Apolipoprotein E (ApoE), amyloid-beta (Aß) and tau, all preferentially localize to and affect synapses.

We hypothesize that their convergent biology occurs at the level of synaptic endosomes of vulnerable neurons in the early cellular phase of AD.

Given the recent but still modest benefit of Aß immunotherapy for AD, we believe that experimental work can further optimize this line of therapy by better understanding and targeting the specific pool of Aß that initiates and continues to promote synapse damage during the course of AD.

Here we propose to delineate cellular mechanisms linking ApoE, Aß and tau in a pathway centered on synaptic endosome biology.

ApoE4 is the most important genetic risk factor for AD; remarkably we showed that it targets synapses when added to neurons.

We previously also first showed that the disease-linked Aß42 begins to accumulate in synaptic endosomes in AD and that AD-like phospho-tau alterations initiate in such Aß42 accumulating terminals.

Here we propose cell and pathological studies to delineate alterations in the endocytic trafficking and lipid composition by ApoE4 and mechanistic/therapy studies relating ApoE, Aß & tau to early AD synaptic dysfunction.