Figure 2.

Generic age-related cellular stress and specific proteopathic abnormalities exert reciprocal cross-amplifying detrimental effects on synaptic plasticity and neuronal viability. During aging, neurons experience reduced energy availability (e.g., mitochondrial dysfunction and reduced glucose transport), increased levels of oxidative stress, perturbed cellular calcium homeostasis, impaired autophagy, and inflammation. The latter adverse changes are exacerbated by a reduced ability of neurons to respond adaptively to stress. The aggregation and associated neurotoxic activities of proteopathic proteins (Aβ, Tau, TDP-43 and α-synuclein) are promoted by metabolic, oxidative and calcium-related stress and impaired autophagy/protein degradation. Thus, cross-amplifying neurodegenerative processes result in synapse dysfunction, degeneration and neuronal death, resulting in dementia.