Alzheimer’s disease patients show progressive and irreversible memory and cognitive impairments, ultimately leading to the loss of their autonomy. This disabling disease is the first cause of dementia in the elderly population. Histopathological lesions include extracellular senile plaques mainly composed of a set of hydrophobic peptides referred to as amyloid β-peptides (A β), intracellular neurofibrillary tangles due to abnormally phosphorylated tau protein, local inflammation characterized by activated microglia and astrocytes, and neuronal loss
. Several risk factors such as aging, brain insults (stroke, traumatic injury), cardiovascular diseases (hypertension), or metabolic diseases (diabetes mellitus, hypercholesterolemia, obesity)
 as well as genetic risk factors
 have been identified but the etiology of the disease is far from being fully understood.
Aβ peptides composing the core of senile plaques are mainly produced by neuronal cells
 and are proteolytically derived from a transmembrane precursor protein, the βamyloid precursor protein (βAPP). βAPP undergoes subsequent cleavages by β- and γ-secretases that ultimately generate Aβ peptides. An alternative and prominent processing of βAPP by α-secretase takes place in the middle of the Aβ domain of βAPP and is regarded as a physiological non-amyloidogenic pathway
Even if the etiology of AD is still a matter of discussion, it is generally admitted that, if not acting as the initial trigger, Aβ peptides at least contribute to AD pathogenesis
. This reasonable statement is supported by genetic data. Thus, mutations responsible for early onset and aggressive AD cases affect three genes encoding proteins involved in Aβ production, namely βAPP, and presenilin 1 and 2
. All these mutations modulate the endogenous levels or nature of Aβ peptides
. More recently, an additional genetic clue came from the observation that a novel mutation on βAPP that partly prevents its β-secretase-mediated cleavage and thereby reducing Aβ load, indeed protected bearers from AD in an Icelanders cohort
Various Aβ peptides species are found in senile deposits as well as inside cells. Their nature and length can vary drastically. Genuine “full length” Aβ peptides, that are Aβ1-40 or Aβ1-42, can undergo a variety of secondary proteolytic cleavages including N-terminal truncation and cyclisation
[9, 10]. Moreover, monomeric soluble Aβ peptides could associate to form small soluble aggregates including oligomers and protofibrils. Soluble oligomeric species apparently display higher toxic potential for cells than Aβ monomers
[11, 12]. Therefore, the pathology likely results from modifications of the nature and concentration of Aβ peptides, an alteration of their biophysical properties and aggregated state, and a change in their subcellular production and accumulation that are likely underlying Aβ-associated toxicity.
In sporadic cases of AD, there is no evidence for an up-regulation of Aβ production and it is widely admitted that Aβ accumulation derives from impairment/alteration of its degradation/clearance. Amyloid peptides are mainly degraded enzymatically by neprilysin, but also and, likely to a lesser extent, by insulin degrading enzyme (IDE), endothelin-converting enzyme (ECE), angiotensin-converting enzyme (ACE), and plasmin
. Neprilysin mRNA and proteins are reduced in brain areas vulnerable to amyloid deposits
 as is neprilysin activity in AD brains
βAPP and its proteolytic fragments are involved in complex networks and several feedback loops have been suggested
. Furthermore Aβ would be able to induce its own production. Thus, the treatment of human NT2N neurons with Aβ peptide increased βAPP processing and production of Aβ peptides
. Aβ peptide can activate its own production by binding to the promoters of βAPP and BACE1, as Aβ has been recently shown to display transcription factor properties
[18, 19]. Furthermore, more related to the purpose of the present review, Aβ can also indirectly activate its production by generating various cellular dysfunctions, as detailed below.