**8. Conclusions**

by promoting Aβ degradation. Different studies have been performed finding that rapamycin reduces the accumulation of Aβ levels and fibrillar aggregates approximately 40–50% in

Morphological evidence shows that APP and Aβ peptide are colocalized with LC3-positive autophagosomes and autophagy induction shows a greater colocalization of Aβ in autophagic vacuoles, suggesting a more active degradation [68]. However, the mechanism by which autophagy can degrade extracellular amyloid plaque content is unknown. But autophagic process of microglia (the resident macrophages in the brain) seems to play an important role. The degradation of extracellular amyloid content through microglia involves at the first step phagocytosis; once Aβ peptide is in the cytosol it is exposed to be recognized by LC3-II via optineurin (an adaptor protein). LC3-II/OPTN recognition allows Aβ degradation via the

The exact pathology of AD is still unknown, but it is widely believed that the deposition of Aβ is one of the main causes leading to the degeneration and death of neurons. So, finding alternatives that avoid Aβ accumulation or enhance its degradation could be a strong thera‐ peutic target. In this sense, autophagy seems to be the first line of defense to face accumulation but it is not clear how autophagy dysfunctions are related to Aβ aggregation or if Aβ over‐

Some observations have demonstrated that a large number of autophagic vacuoles are observed in dystrophic neuritis before extracellular Aβ depositions in the neurons of AD patients and murine models of AD [70], but recently it has been demonstrated that Aβ monomers and oligomers differentially modulate autophagy in neurons. In a different way, monomers stimulate autophagy increasing autophagosome rates and the elevation of LC3-II protein levels, but at the same time monomers impaired lysosomal pathway affecting the autophagy flux. These events resulted in autophagosome accumulation. On the other hand, Aβ oligomers cause a less pronounced increase in LC3-II protein levels and does not affect the autophagy flux [58], suggesting that defects in autophagy could be the result of an increase in

Enhancing autophagic clearance of toxic protein aggregates through rapamycin or trehalosa ameliorates protein aggregation, neuron survival, and this is reflected in the improvement of cognitive skills. However, converging evidence suggests that improvement in autophagic flux through stimulation is a promising therapeutic intervention, and this field is still developing. In other words, there are barely some studies showing the degradation by autophagy of the N-truncated beta amyloid peptide [71–74]. Recently, it has been determined that pE3-Aβ is strongly reduced in the TgCRND8 mice fed with a normal diet supplemented with the antioxidant Oleurupein (OLE) and that such a decrease likely reflects the parallel reduction of QC expression. In addition, their model of (Aβ) peptide deposition displayed strongly improved performance in behavioral and cognitive tests, reduced inflammatory response, and recovered dysfunctions of transgene-induced long-term potentiation (LTP) in the CA1

3XAD-Tg mice and APP transgenic mice [67].

180 Update on Dementia

autophagic–lysosomal system [69].

amyloid monomers.

production directly induces autophagy defects.

**6.5. Differential autophagy activation by monomers and oligomers**

As discussed in this chapter, there are some βA clearance mechanisms that are altered in Alzheimer´s disease. A large number of evidence exists about the βA1-42 clearance mecha‐ nism. However, despite of this, there is a lack of evidence related to the βA3-42 and βA11-42 degradation mechanisms. The principal βA variants detected in the human brain are A1-40 and A1-42; however, a significant proportion of AD brain A also consists of N-terminaltruncated species and the latest hypothesis pointing that they are seeding species. For this reason, N-terminal peptides represent highly desirable and abundant therapeutic targets.

We have an urgent need to perform immunotherapy strategies directed against N-truncated/ pyroglutamate-modified βA peptides and consider them for vaccine development for AD. These kinds of analysis may provide promising diagnostic and therapeutic tools, targeting all pathological amyloid species involved in AD in the future.

In other words, autophagy is a hot topic in the recent years, enhancing autophagic clearance of toxic protein aggregates through rapamycin or trehalosa ameliorates protein aggregation and neuron survival, and this is reflected in the improvement of cognitive skills. However, converging evidence suggests that the improvement in the autophagic flux through stimula‐ tion is a promising therapeutic intervention that is still developing. Importantly, the combi‐ nation of different strategies targeting simultaneously different pathological pathways, "systems therapeutics", might be more appropriate for a multifactorial disease like AD. For example, we should try to design an anti-βA, anti-tau, anti-inflammatory, anti-oxidative stress, and autophagy enhancing strategy in preclinical trials with a hope to translate them to human research.

Interestingly, there is no information about the presence of the N-truncated species of beta amyloid peptides in the eye. The big question is: Why? Is not there relevance? Or only has not been studied? More research in this topic is urgently needed in order to improve the quality of life of patients with AD.
