Alzheimer's Disease (AD) is the most common cause of dementia in the elderly, and is characterized by a progressive loss of cognitive functions. The histopathology of AD includes accumulations of extracellular Aβ peptides (neuritic plaques) and intra-neuronal hyperphosphorylated tau (neurofibrillary tangles) (Hardy and Selkoe, 2002
). Several lines of evidence suggest that cognitive failure is linked to the generation and deposition of neurotoxic species of Aβ derived by secretase cleavage of the a
rotein (APP). APP is an integral type I membrane protein that is trafficked through a constitutive secretary pathway and processed at the cell surface, trans-Golgi network (TGN) and endocytic organelles (Thinakaran and Koo, 2008
). β A
nzyme1 (BACE1) and the γ-secretase complex, which includes presenilin1 (PS1), Nicastrin, Aph-1 and Pen2, are also present in ER, TGN, endosomes, and on the cell surface (De Strooper and Annaert, 2010
; Small and Gandy, 2006
). Amyloidogenic processing of APP is thought to occur in endosomes, but the precise trafficking events remain unclear.
Aβ generation can be modulated by neural activity in the interstitial fluid (ISF) in vivo
(Cirrito et al., 2005
) or in hippocampal slices (Kamenetz et al., 2003
), suggesting that a substantial fraction of Aβ generation is dependent on activity; however, the contribution of activity-dependent Aβ generation to amyloid deposition in vivo
is as yet unclear. Aberrant activity in the hippocampus “default pathway” is linked to cognitive decline in patients with AD (Buckner et al., 2005
). By contrast, behavioral activation is reported to reduce plaque load in a mouse model of AD (Lazarov et al., 2005
), and epidemiological studies suggest that cognitive activity is protective for AD (Cracchiolo et al., 2007
). The absence of a molecular understanding of how activity increases Aβ accumulation has limited deeper appreciation of the contribution of activity to AD pathogenesis.
Our previous studies have focused on cellular immediate early genes (IEG) as potential mediators of protein synthesis dependent memory. Among them, Arc is a neuron-specific, postsynaptic protein that interacts with endophilin and dynamin, and contributes to an endocytic pathway that accelerates removal of AMPA receptors from excitatory synapses (Chowdhury et al., 2006
). Arc is required for multiple forms of synaptic plasticity that depend on its endocytic function including homeostatic scaling (Shepherd et al., 2006
) and mGluR-LTD (Park et al., 2008). Arc is an intriguing candidate that could participate in activity-dependent Aβ generation since endocytic pathways are important for regulation of BACE1 activity (Huse et al., 2000
). Moreover, dominant negative dynamin, which blocks endocytosis, reduces Aβ levels in ISF by as much as 70%, and prevents activity-dependent increases in Aβ (Cirrito et al., 2008
Here, we report that Arc is required for activity-dependent increases of Aβ generation, and reveal a role for Arc in postsynaptic trafficking and processing of APP that appears relevant to the pathogenesis of AD. Arc directly binds the N-terminus of PS1, the catalytic subunit of the γ-secretase complex, and these proteins co-localize in early/recycling endosomes within dendrites. Interruption of the Arc-PS1 interaction prevents activity-dependent increases of Aβ, and cell biological studies support a role for Arc in trafficking γ-secretase to vesicles that process APP. Arc-dependent Aβ generation contributes to plaque deposition in a mouse model of AD, and Arc expression is significantly elevated in the medial prefrontal cortex of patients with pathologically confirmed AD. Together, these findings demonstrate that Arc-dependent mechanisms, which are known to control synaptic strength, also control activity-dependent generation of Aβ that is relevant in the pathogenesis of AD.