Amyloid β 1–42 deposits do not lead to Alzheimer’s neuritic plaques in aged dogs

Alzheimer’s disease (AD) is neuropathologically defined by the deposition of amyloid in the form of senile plaques, congophilic angiopathy and neurofibrillary tangles (reviewed in [1]). The major constituent of both senile plaques and congophilic angiopathy is a 39–44 amino acid residue peptide, amyloid β (Aβ) [2–8]. Aβ is found, at low concentrations, as a normal constituent of biological fluids, where it is called soluble Aβ (sAβ) [9-12]. sAβ is predominantly Aβ1–40, although shorter and longer sequences exist, including Aβ1–28 and Aβ1–42 [13]. Neuritic plaque amyloid was first sequenced in 1985 [3] and was found to extend mainly to Aβ42}43, while vascular amyloid was initially reported to extend to Aβ1–28 [2] and later to Aβ 39}40 [5,14]. This heterogeneity at the C-terminus of Aβ was attributed to differences in the local tissue processing. More recent reports using different techniques have also found Aβ42 in vascular amyloid deposits [15]. Aβ in both types of amyloid deposits has a predominantly β-sheet structure; on the other hand, sAβ presumably is more random-coil and}or α-helical. An early stage in the development of senile plaques are ‘preamyloid’ or diffuse plaques [16–18]. This is based in part on studies in Down’s syndrome (DS) individuals, where diffuse plaques occur at a very early age, preceding the development of senile plaques [19–21]. Preamyloid deposits are ‘cotton-wool-like areas ’ that are immunoreactive with anti-Aβ antibodies, have irregular borders and are associated with few dystrophic neurites [16–18]. Preamyloid deposits are not stained by Congo Red or Thioflavine S, and ultrastructurally are composed mainly of amorphous, non-fibrillar material. Aged individuals can have large numbers of diffuse plaques without any signs of neuronal dysfunction or dementia [22–24]. We hypothesize that senile plaque formation can be viewed as having at least two major steps, whereby sAβ first undergoes a conformational change and aggregates into preamyloid deposits and this is followed by a gradual process of compaction and fibrillization over many years. It is only in this form that significant toxicity has been documented with synthetic