Peptides as drug candidates against Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia among people aged 65 and older. In fact, nearly 50% of all people aged 85 and older are thought to have AD. It is thus of high importance to develop therapies to combat the disease and alleviate the devastating outcome. The drugs currently available treat one of the disease symptoms, the decline in acetylcholine, by way of inhibiting the acetylcholinesterase pathway that leads to acetylcholine breakdown. However, this apparently slows the disease symptomology only for a limited time period. Here, neuropepticle/peptide involvement and potential therapy in AD will be approached at several different levels including (1) neuropeptides and AD; (2) amyloid precursor protein processing and toxic beta amyloid (A-beta) accumulation; (3) peptide vaccination against toxic A-beta aggregation; (4) peptides in the inhibition of tau phosphorylation and the formation of toxic neurofibrillary tangles; and most emphasis will be placed on (5) neuroprotective peptides, from vasoactive intestinal peptide (VIP) to activity-dependent neuroprotective protein (ADNP), NAP and activity-dependent neuroprotective factor (ADNF). Previous studies facilitated the characterization of a lead peptide termed NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln, single letter code, NAPVSIPQ). Preclinical experiments show that NAP protects neurons against numerous toxins and cellular stresses including the AD neurotoxin, excitotoxicity, the toxic envelope protein of HIV, electrical blockade, oxidative stress, dopamine toxicity, decreased glutathione, and tumor necrosis factor-associated toxicity. NAP also has neuroprotective activity in a variety of animal models including the learning-deficient apolipoprotein E knockout mice (a model related to AD), mouse paradigms of traumatic head injury (risk factor for AD) and fetal alcohol syndrome (oxidative stress), and rat models of cholinotoxicity and stroke. NAP has a short structure, is active at unprecedented low concentrations (femtomolar), is water soluble, bioavailable, easily delivered via intranasal inhalation, and is unusually stable. No NAP toxicity has been observed to date. Thus, NAP is poised to be developed as a novel Alzheimer's disease therapeutic.