Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid β (Aβ) accumulation, extracellular Aβ deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD. IntroductionFamilial Alzheimer disease (AD) mutations increase the toxicity and amyloidogenicity of the amyloid β (Aβ) peptide, placing disruption of amyloid precursor protein (APP) metabolism and Aβ production at the center of AD pathogenesis (1). However, less than 2% of AD cases are caused by autosomal-dominant mutations. Familial AD caused by these mutations and the remaining nondominant sporadic AD cases are pathologically similar. Therefore, factors that disrupt APP metabolism and Aβ production, such as increased APP transcription, increased production of amyloidogenic Aβ (2), and decreased APP degradation, may contribute to the pathogenesis of sporadic AD as well.The etiology of AD is distinct from that of other neurodegenerative diseases, such as Parkinson disease and Huntington disease (HD), but all are characterized pathologically by the presence of abnormal protein aggregates and neuronal death (3, 4). Protein aggregates may form by abnormal folding or proteolytic processing of proteins or by the disturbance of intracellular protein degradation pathways (3,5). Autophagy is involved in the intracellular degradation of aggregation-prone α-synuclein (6) and huntingtin

Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.

Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-␤ (A␤) peptides, which are derive from processing of the ␤-amyloid precursor protein (APP), better named amyloid-␤ precursor protein (A␤PP), by secretases. The A␤PP intracellular domain (AID), which is released together with A␤, has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating A␤PP processing are poorly understood. As cleavage of other ␥-secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind A␤PP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with A␤PP. Interestingly, 17 amino acids corresponding to the NH 2 -terminal portion of A␤ are necessary for this interaction. Moreover, BRI2 expression regulates A␤PP processing resulting in reduced A␤ and AID levels. Altogether, these findings characterize the BRI2-A␤PP interaction as a regulatory mechanism of A␤PP processing that inhibits A␤ production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on A␤PP processing would define dysregulation of A␤PP cleavage as a pathogenic mechanism common to AD, FDD, and FBD. A␤PP1 is an ubiquitous type I transmembrane protein (1, 2) that undergoes a series of endoproteolytic events (3-5). A␤PP is first cleaved at the plasma membrane or in intracellular organelles by ␤-secretase (6). While the ectodomain is released extracellularly (sAPP␤) or into the lumen of intracellular compartments, the COOH-terminal fragment of 99 amino acids (C99) remains membrane bound. In a second, intramembranous proteolytic event, C99 is cleaved, with somewhat lax site specificity, by the ␥-secretase. Two peptides are released in a 1:1 stoichiometric ratio: the amyloidogenic A␤ peptide, consisting of 2 major species of 40 and 42 amino acids (A␤40 and A␤42, respectively), and an intracellular product named AID or AICD, which is very short-lived and has been identified only recently (7-9). In an alternative, nonamyloidogenic proteolytic pathway, A␤PP is first processed by ␣-secretase in the A␤ sequence leading to the production of the sAPP␣ ectodomain and the membrane-bound COOH-terminal fragment of 83 amino acids (C83). C83 is also cleaved by the ␥-secretase into the P3 and AID peptides. While A␤ is implicated in the pathogenesis of Alzheimer disease, AID mediates most of the A␤PP signaling functions. A pathogenic role for A␤PP processing in AD has been ascertained by the finding that mutations in presenilins (10 -13), key components of the ␥-secretase, and A␤PP (14) cause autosomal dominant familial forms of AD. Thus, because of its biological and pathological import...