The neuroprotective and anti-amyloidogenic properties of Chlorhexidine hydrochloride hNGFP61S/R100E mutant demonstrated in APPxPS1 transgenic mice are noteworthy. In this mouse model, the expression of mutated human APP and PS1 is the first cause of neurodegeneration. The administration of hNGFP61S/R100E was performed at an age when memory deficits have not yet started and amyloid plaque deposition is in the initial phase. This allowed to study the effects of hNGFP61S/R100E at very early stages of the progressive neurodegeneration, showing that in APPxPS1 the hNGFP61S/R100E mutant was able to prevent learning and memory defects and to greatly reduce Ab deposition. In addition, by using a conformation specific antibody anti-Ab oligomers, we demonstrated that hNGFP61S/R100E prevents or reduces the accumulation of Ab oligomers, considered the earliest and most synaptotoxic forms of Ab. Thus, hNGFP61S/R100E exerts an anti-amyloidogenic effect in vivo, in a disease-relevant FAD-based model. From a mechanistic point of view, this might involve a generalized neuroprotective activity by the neurotrophin, at multiple levels, by slowing the generation of Ab peptide and Ab oligomers, by reducing the microgliosis and astrogliosis and/or, possibly, by increasing the clearance of Ab peptides, thereby leading to the observed reduced plaque load and Ab oligomer levels. The observed effects on astrocytes and microglia are consistent with both these cell types expressing TrkA and p75NTR NGF receptors, in normal and pathological conditions. Reactive astrocytes, present in APP xPS1 brain due to amyloid pathology, also express higher levels of TrkA in human AD. We found a reduction of both microgliosis and Atropine sulfate astrocytosis in hNGFP61S/R100E treated APPxPS1 brains, suggesting that the ensuing reduced neuroinflammation might contribute to remove an environment permissive for the buildup of amyloid pathology and neurodegeneration. Further studies are required to verify whether the activation of TrkA signaling by hNGFP61S/R100E might regulate the known mechanisms of internalization and Ab degradation by astrocytes. The selective modulation of TrkA and p75NTR downstream signaling pathways might also contribute to the neuroprotective action of hNGFP61S/R100E. Indeed, while the activation of the Akt signaling pathway, which is preserved by hNGFR100 mutants, is required for a neuroprotective action and is downregulated by soluble Ab oligomers, Erks and c-jun activation have been linked to neurodegeneration and cell death. Oligomeric assemblies of Ab have been found to up-regulate phospho-Erks, which, in turn, can lead to abnormal phosphorylation of tau, generation of dystrophic neurites and progressive neuronal degeneration. Similarly, up-regulation of c-jun has been linked to cell death and tau phosphorylation in AD, and its down-regulation prevents the amyloidogenic cleavage of APP and the formation of amyloid plaques in AD mouse models. Thus, the decreased activation of Erks and c-jun by hNGFP61S/ R100E would uncouple their involvement in a positive feedback neurodegenerative loop and facilitate the down-regulation of the effects by the aberrant APP processing. Further studies are required at more later stages of neurodegeneration, when conflicting results about the “benefits” of Erks activation have been reported. The possibility of hNGFP61S/R100E acting directly on APP processing and its direct consequences, such as the vicious cycle linking Ab to the proNGF/NGF balance should also be considered for future investigation. In this respect, it should be noted that APPxPS1 mice show a defect in NGF retrograde axonal transport by cholinergic neurons.