Basic Science and Pathogenesis.

Background: Adults with Down syndrome (DS) develop Alzheimer's disease (AD) brain pathology by their 40s due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and most develop clinical symptoms by age 50-60. Inheritance of the apolipoprotein E (apoE) ε4 allele (APOE4) is the strongest risk factor for AD besides age, whereas the ε3 allele (APOE3) does not change AD risk. The APOE4 genotype is associated with earlier and more rapid cognitive decline in both typical AD and DS-associated AD (DS-AD); however, understanding of the associated mechanisms is lacking.

Increased / expression offsets Alzheimer Aβ-mediated toxicity and cognitive dysfunction.

Previously, we found that amyloid-beta (Aβ) competitively inhibits the kinesin motor protein KIF11 (Kinesin-5/Eg5), leading to defects in the microtubule network and in neurotransmitter and neurotrophin receptor localization and function. These biochemical and cell biological mechanisms for Aβ-induced neuronal dysfunction may underlie learning and memory defects in Alzheimer's disease (AD). Here, we show that KIF11 overexpression rescues Aβ-mediated decreases in dendritic spine density in cultured neurons and in long-term potentiation in hippocampal slices.