**6. Concluding remarks**

neurodegeneration and memory loss. As part of its mechanism of action, HDHA dampens the binding affinity of oligomeric and fibrillar Aβ to lipid-raft membrane domains. Moreover, it enhances the unfolded protein response (UPR) and autophagy in neuron-like cells, which in turn may promote neuronal survival [160, 161]. In this sense, although the molecular role of autophagy in AD is complex and still largely unknown, it is thought that activation of salvage autophagy would avoid the intracellular accumulation of Aβ and its precursors by reducing the neuritic pathology (see **Figure 2**) [162, 163]. Therefore, the pleitropic effects of HDHA have proven beneficial to treat AD, suggesting that its molecular target is an upstream entity such as the membrane lipid bilayer. Thus, the normalization of the PE, DHA, cholesterol, and SM content mediated by HDHA would restore membrane lipid structure, which in turn would regulate amyloidogenic secretase activity tau phosphorylation and neuronal degeneration.

152 Update on Dementia

**Figure 4.** Proof of concept for the use of HDHA in AD mice and the proposed molecular mechanism of action. (A) Diagrams showing representative outlines of control and AD mice (5xFAD mice) that received HDHA or the vehicle alone, in the Radial Arm Maze test (RAM). A black point at the end of one arm represents where the mice find a food pellet. (B) Quantitative analysis of test performance is addressed by quantifying working (reentry of an arm already visited) and reference (entry into an unbaited arm) memory errors. Both parameters increased significantly in AD mice while HDHA treatment prevented such behavioral impairment until cognitive scores were almost totally reverted to those of the controls. Bars represent the mean ± SEM. One-way ANOVA followed by Bonferroni's post hoc test: \*p < 0.05, difference relative to healthy controls; #: p < 0.05 difference relative to the untreated AD group. C) Postulated mechanism of action for HDHA. HDHA enriches brain membranes in PE carrying DHA and other long PUFAs. These lipid changes may influence the structure of the cell membrane by promoting the appearance of liquid-disordered prone structures and potentially preventing AD-related cell signaling by: (i) downregulating APP amyloidogenic proc‐ essing and Aβ-induced tau protein hyperphosphorylation; and (ii) decreasing neuron vulnerability to extracellular tox‐ ic agents such as oligomeric Aβ. Together, this evidence supports a neuroprotective role of HDHA that may be

associated with the improved cognitive capabilities observed in AD mice. Adapted from [159, 160].

After adipose tissue, the human brain is the organ with the largest amount of lipids in the body. There is compelling evidence that lipid homeostasis is altered in AD, suggesting that the plasma membrane lipid composition and structure plays a critical role in the pathophysi‐ ology of AD and hence in its therapy. Therefore, lipid alterations might be responsible for other downstream neuropathological hallmarks of AD, including amyloid and neurite pathologies, as well as inflammation and neuron loss, which eventually causes the cognitive deterioration evident in patients with AD. Accordingly, a number of clinical trials have been set up to investigate how the regulation of cholesterol and PUFA hydroxyl derivatives such as HDHA may constitute promising therapeutic approaches to treat this devastating condition.
