a b s t r a c tAlthough widely explored, the pathogenesis of Alzheimer's disease (AD) has yet to be cleared. Over the past twenty years the so call amyloid cascade hypothesis represented the main research paradigm in AD pathogenesis. In spite of its large consensus, the proposed role of b-amyloid (Ab) remain to be elucidated. Many evidences are starting to cast doubt on Ab as the primary causative factor in AD. For instance, Ab is deposited in the brain following many different kinds of injury. Also, concentration of Ab needed to induce toxicity in vitro are never reached in vivo. In this review we propose an amyloid-independent interpretation of several AD pathogenic features, such as synaptic plasticity, endo-lysosomal trafficking, cell cycle regulation and neuronal survival.

Evidence indicates that the degeneration of basal forebrain cholinergic neurons may represent an important factor underlying the progressive cognitive decline characterizing Alzheimer's disease (AD). However, the nature of the relationship between cholinergic depletion and AD is not fully elucidated. This study aimed at clarifying some aspects of the relation existing between deficits in cerebral energy metabolism and degeneration of cholinergic system in AD, by investigating the neuronal metabolic activity of several cortical areas after depletion of basal forebrain cholinergic neurons. In cholinergically depleted rats, we evaluated the neuronal metabolic activity by assaying cytochrome oxidase (CO) activity in frontal, parietal and posterior parietal cortices at four different time-points after unilateral injection of 192 IgG-saporin in the nucleus basalis magnocellularis. Unilateral depletion of cholinergic cells in the basal forebrain induced a bilateral decrease of metabolic activity in all the analyzed areas. Frontal and parietal cortices showed decreased metabolic activity even 3 days after the lesion, when the cholinergic degeneration was still incomplete. In posterior parietal cortex metabolic activity decreased only 7 days after the lesion. The possible molecular mechanisms underlying these findings were also investigated. Real-time PCR showed an increase of CO mRNA levels at 3, 7 and 15 days after the lesion both in frontal and parietal cortices, followed by normalization at 30 days. Western Blot analysis did not show any change in CO protein levels at any time-point after the lesion. Our findings support a link between metabolic deficit and cholinergic hypofunctionality characterizing AD pathology. The present model of cholinergic hypofunctionality provides a useful means to study the complex mechanisms linking two fundamental and interrelated phenomena characterizing AD from the early stages.

On page 642, paragraph 2, right column, line 12 the following reference should be inserted: [170]. Sorrentino, G. and Bonavita, V. (2007) Neurodegeneration and Alzheimer's disease: the lesson from tauopathies. Neurol. Sci. 28, 63-71.The first 19 lines of paragraph 4.2, on page 645, should read: ''APP seems to have a role in neural degeneration mostly as it is processed, rather than through Ab formation [15]. For instance, there is now broad evidence of the neuroprotective and neuroproliferative role of sAPPa in adult neuron [92,93]. Moreover, mice lacking APP show a smaller brain size [94], and sAPPa expression alone reverses this effect [95]. Furthermore, it has been showed that ERK-induced axon growth is prompted by sAPPa and sAPPb (generated in a 9:1 ratio) and that amino terminal fragments of APP can shift stem cell growth toward a neural phenotype [96]. Overall, all this evidence seems to suggest that APP processing might be an important inductor of neural stem cell differentiation [15] (Fig. 2).'' Lines 19-42, on page 646, paragraph 6.0, should read: ''The association between AD and ApoE is documented by observations of structural variants of the ApoE protein [133]. In humans, ApoE4 expression increases as a consequence of neuronal damage and a neuron-specific proteolysis, guided by astrocytes, takes place [151,152]. More specifically, ApoE4, cut by ApoE Cleaving Enzyme (AECE) and missing the 272-299 residues (D272-299), is not processed by the secretory pathway as it translocates to the cytosol [133]. On the other hand, D272-299-ApoE4 is integrated in the neurofibrillary tangle-like structures [152]. Accordingly, mice overexpressing cleaved-ApoE4 die within 4 months as they form AD-like neurofibrillary tangles. Furthermore, when mutated ApoE is expressed at lower levels, learning and memory deficits are observed at 6-7 months [153]. In addition, in Neuro-2a cell line, the D272-299-ApoE4 impairs complex III and IV respiratory functions [154], and mice expressing the same variant of ApoE display impaired axonal transport, with mitochondria accumulation in bulb-like dilations [133,155]. '' http://dx